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1
Taylor, Anna. "Peripheral mechanisms of trigeminal neuropathic pain." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97105.
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Trigeminal neuropathic pain is a unique type of neuropathic pain resulting from damage to primary afferents of the trigeminal nerve that innervates the head and neck region. It is characterized by intractable, unremitting pain in the absence of any overt tissue damage, and represents a significant clinical and societal burden. A thorough understanding of the mechanisms driving this condition is required to adequately treat, and ideally cure, this condition. The skin of the lower lip is innervated by several classes of primary afferents, including myelinated Aβ fibers, thinly myelinated Aδ fibers, and unmyelinated C fibers, which together are able to transduce the variety of innocuous and noxious stimuli encountered in the environment. Nociceptive stimuli are largely mediated by the unmyelinated C fibers, which have been further divided into 2 groups based on neurochemical and anatomical criteria, called the peptidergic and non-peptidergic C fibers. Given that nerve lesions initiating neuropathic pain conditions most often occur in the periphery, changes in the peripheral nervous system following nerve injury are particularly relevant in driving this aberrant pain condition. Therefore, the overall objective of this thesis is to explore the peripheral changes in an animal model of trigeminal neuropathic pain. The results of this thesis are presented in three chapters. The pattern of innervation of non-peptidergic C fibers in the skin of uninjured rats has been described, as well as how this fiber population changes following nerve injury. Concomitant ectopic autonomic fibers were observed in close apposition to the regenerating sensory fibers, and correlated with the behavioral phenotype of the animals. GDNF levels in the skin rapidly increased following nerve injury, and provided a possible mechanism for the ectopic parasympathetic fibers and regenerating non-peptidergic C fibers. Ablation of the non-peptidergic C fibers led to specific sprouting of parasympathetic fibers, but no change in behavior, however ablation of non-peptidergic fibers in neuropathic animals led to an exacerbated pain response. These results suggest an important role for non-peptidergic fibers and autonomic sprouting in neuropathic pain, and identifies GDNF as a potential factor for mediating these changes.La douleur trigeminale neuropathique est une forme unique de douleur qui résulte d'un dommage aux afférents primaires du nerf trijumeau innervant la région de la tête et du coup. Cette douleur constante qui se manifeste en l'absence d'un dommage aux tissus périphériques représente un fardeau social et économique important. Une compréhension rigoureuse des mécanismes qui mènent à cette condition sera nécessaire pour mieux la traiter et préférablement la guérir.La peau de la lèvre inferieure est innervée par des afférents primaires appartenant à différentes classes, incluant les fibres myélinisées Aβ, les fibres légèrement myélinisées Aδ, ainsi que les fibres C non myélinisées. Ensemble, ces fibres peuvent transmettre une variété de stimuli nociceptifs ou inoffensifs tels que rencontrés dans l'environnement. Les stimuli nociceptifs sont majoritairement transmis par les fibres C non myélinisées, lesquelles peuvent être divisées en 2 catégories, peptidergiques ou non peptidergiques, selon des critères neurochimiques et anatomiques. Puisque les lésions nerveuses qui déclenchent la douleur neuropathique se produisent le plus souvent en périphérie, les changements au niveau du système nerveux périphérique sont centraux au développement de la condition douloureuse. Ceci étant dit, l'objectif général de cette thèse est d'explorer les changements périphériques qui se produisent dans un model animal de douleur trigeminale neuropathique.Les résultats de cette thèse sont présentés dans trois chapitres. L'innervation de la peau par les fibres C non peptidergiques chez le rat normal a d'abord été décrite. Ensuite, les changements subis par cette population suivant un dommage au nerf ont été documentés. Suite à un dommage nerveux périphérique, des fibres autonomiques ectopiques ont été observées en proximité des fibres sensorielles en régénération, et ce changement corrélait temporellement avec le phénotype comportemental des animaux. Les niveaux cutanés de GDNF ont rapidement augmenté après le dommage nerveux, fournissant un mécanisme potentiel permettant la régénération des fibres C non peptidergiques et la migration ectopique des fibres parasympathiques. L'ablation des fibres C non peptidergiques a déclenché la pousse des fibres parasympathiques sans changer le comportement des animaux. Par contre, l'ablation de ces fibres chez des animaux neuropathiques a exacerbé la réponse douloureuse de ceux-ci.Ces résultats suggèrent une participation importante des fibres C non peptidergiques et de la migration autonomique dans la douleur neuropathique. De plus, GDNF est rapporté comme étant un facteur pouvant produire ces changements.
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Wallace, Victoria C. J. "Peripheral nerve demyelination and neuropathic pain." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/27605.
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Chronic neuropathic pain, characterised by allodynia (perception of innocuous stimuli as painful) and hyperalgesia (facilitated responses to painful stimuli), is poorly understood and is usually resistant to classical analgesics. Such abnormal pain phenomena can be associated with human demyelinating conditions such as Charcot-Marie-Tooth disease. Using mouse models of peripheral nerve demyelination, we have provided evidence for the consequent establishment of neuropathic pain and investigated possible underlying mechanisms. The first model investigated was the Prx-null mouse. The murine periaxin gene (Prx) is expressed in Schwann cells and encodes L- and S-periaxin, two abundant PDZ-domain proteins thought to have a role in stabilisation of myelin in the peripheral nervous system (PNS). Prx-null mice show progressive demyelination in peripheral nerves and electrophysiological investigations indicate the presence of spontaneous action potential discharge; abnormal activity thought to be critical for the development of persistent pain states. Consistent with the time course of demyelination, Rrx-null mice display an increased behavioural reflex sensitivity to cutaneous mechanical and noxious thermal stimulation. To further investigate the link between demyelination of peripheral nerves and neuropathic pain, we have also characterised a novel model of focal peripheral nerve demyelinating neuropathy. Focal demyelination of the sciatic or saphenous nerve was induced with lysolecithin (lysophosphatidylcholine) and resulted in an increased behavioural reflex sensitivity to both thermal and mechanical tests, peaking at 9-14 days following treatment. Nerve morphology was investigated using light and electron microscopy, which revealed 30-40% demyelination of the treated nerve, (without lysolecithin-treated axon loss) coinciding with peak behavioural changes. Changes in the excitability of saphenous nerves were revealed, with spontaneous action potential discharge of 2-3 impulses per second present at peak behavioural change. No associated change in peripheral activation thresholds or conduction velocity was observed. In both models, immunohistochemical investigations revealed no cell loss in the dorsal root ganglia (DRG) and no evidence for axonal damage. Similar methods revealed changes in the expression of neuropeptide Y, and the sodium channels Nav1.3 and Nav1.8 in DRG neurones. Such changes may account for increased nerve excitability and are known to occur in other models of nerve injury. However, these changes in the demyelinating models occur in a more restricted manner, specifically in the cells of formerly myelinated fibres. Intrathecal injections of the selective NMDA receptor antagonist, [R]-CPP, indicated that NMDA receptor-dependent changes are crucial for the development of a neuropathic pain-like state following peripheral nerve demyelination. Intrathecal administration of pharmacological agents indicated a role for the transcription factor NFkB in the production of the behavioural reflex sensitivity of lysolecithin-treated mice, as well as identifying the endogenous cannabinoid system as an effective inhibitory regulator and potential analgesic target. This study describes the first mouse models of peripheral nerve demyelination designed for the study of neuropathic pain and reveals phenotypic changes in DRG, which may contribute to the development of a neuropathic pain-like state. Therefore, these models may be useful for the evaluation of novel therapeutic targets for the treatment of demyelination-associated neuropathic pain.
3
Liu, Xue Jun. "Peripheral regulation of inflammatory pain and neuropathic pain by adenosine." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66636.pdf.
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Caspani, Ombretta [Verfasser]. "Cold transduction mechanisms during peripheral neuropathic pain / Ombretta Caspani." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1023169932/34.
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Ramer, Matthew Stephen. "Sympathetic and sensory neuronal plasticity, peripheral substrates of neuropathic pain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ31950.pdf.
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Bian, Di. "Peripheral and spinal mechanisms of neuropathic pain in the rat." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284087.
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The Chung peripheral nerve injury model shows consistent allodynia and thermal hyperalgesia, which represent the most common clinical neuropathic pain symptoms. Also clinically relevant, in the Chung model spinal morphine was inactive against tactile allodynia and diminished in potency in acute nociception without spinal/supraspinal antinociceptive synergy. Further, there are increased levels of dynorphin in multiple segmental regions of the spinal cord. This loss of spinal/supraspinal synergy and the spinal antiallodynic effect of morphine is restored by spinal MK-801 or antiserum to dynorphin. It is shown here that spinal transection blocks tactile allodynia, but not thermal hyperalgesia in Chung model rats, suggesting that thermal hyperalgesia involves both spinal and supraspinal circuits, whereas tactile allodynia depends on a supraspinal loop. The c-fiber specific neurotoxin resiniferatoxin before or after Chung surgery abolishes thermal nociception in Chung and sham-operated rats, but not allodynia in Chung model rats. These data suggest that tactile allodynia may be mediated by Aβ-fibers rather than c-fibers, offering a mechanistic basis for the observed insensitivity of allodynia to spinal morphine in Chung model rats. The data also show that PN3 sodium channel protein expression is increased in medium to large diameter neurons in the L4 ipsilateral DRG of Chung rats, and that selective knockdown of PN3 protein in the DRG with specific antisense prevents and reverses allodynia and hyperalgesia in Chung model rats without affecting normal nociceptive functions. Meanwhile, the increased dynorphin level in the spinal cord of Chung model rats returns to normal following spinal PN3 antisense. This suggests that increased PN3 protein in the DRG of Chung model rats may underlie an important mechanism for central sensitization and peripheral ectopic firing after nerve injury. Increased expression of PN3 is also found in the DRGs of diabetic and CFA model rats; knockdown of PN3 reverses allodynia and thermal hyperalgesia in these models. Together, these data suggest that relief from peripheral nerve injury, chronic inflammation, or diabetic neuropathy might be achieved by selective blockade of PN3. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.
7
McCormick, Barry. "Antioxidant protection in mitochondria in chemotherapy-induced neuropathic pain." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229728.
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Neuropathic pain is a common and dose-limiting adverse effect of several cancer chemotherapeutic agents including paclitaxel. Current treatments for chemotherapy-induced peripheral neuropathy (CIPN) are largely ineffective and the pain can persist long after the cessation of the chemotherapy regimen. Whilst the specific underlying mechanisms are not fully understood, oxidative stress and mitochondrial damage are thought to be involved in the development of CIPN. Antioxidants which protect mitochondria may inhibit oxidative stress and protect mitochondrial function more effectively than antioxidants which do not specifically act within mitochondria, and may attenuate CIPN. The overall aim of the study was therefore to determine the effects of mitochondrial-targeted antioxidants on CIPN. This was addressed in two main parts. Firstly, in vitro studies aimed to determine the effects of paclitaxel alone and in combination with mitochondrial-targeted antioxidants melatonin and MitoVitE, and a non-targeted antioxidant, Trolox, on oxidative stress and mitochondrial function in cells. In vivo studies aimed to determine the effects of melatonin, MitoVitE and Trolox in a preclinical rat model of paclitaxel neuropathic pain. In vitro studies used a dorsal root ganglion (DRG) cell line (50B11). Cells were cultured with a range of concentrations of paclitaxel, with or without the addition of melatonin, MitoVitE or Trolox. Several measures of oxidative stress including free radical production, and glutathione levels, and measures of mitochondrial function, including mitochondrial metabolic rate, membrane potential, mitochondrial pore opening and ATP production were made. In vivo studies used a rat model of paclitaxel-CIPN, and assessed the effects of melatonin, MitoVitE and Trolox on behavioural measures of pain. In vitro studies showed that paclitaxel induced oxidative stress and caused mitochondrial damage in the DRG cell line. Compared to paclitaxel alone, cells co-treated with melatonin and MitoVitE had reduced oxidative stress and mitochondrial damage. Co-treatment of cells with paclitaxel and Trolox did not differ from conditions with paclitaxel only. In vivo studies demonstrated that melatonin and MitoVitE attenuated paclitaxel-induced mechanical hypersensitivity, whilst Trolox did not affect behavioural measures of CIPN. These studies suggest that mitochondrial-targeted antioxidants may be useful as a potential treatment strategy for CIPN.
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Erichsen, Helle Kirstein. "Characterisation of the spared nerve injury model of neuropathic pain /." Cph. : The Danish University of Pharmaceutical Scienes, Department of Pharmacology, NeuroSearch, Kongl. Carolinska Medico Chirurgiska Institutet, 2003. http://www.dfh.dk/phd/defences/Hellekirsteinerichsen.htm.
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Klein, Johann, Sahr Sandi-Gahun, Gabriele Schackert, and Tareq A. Jratli. "Peripheral nerve field stimulation for trigeminal neuralgia, trigeminal neuropathic pain, and persistent idiopathic facial pain." Sage, 2015. https://tud.qucosa.de/id/qucosa%3A35439.
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Objective: Peripheral nerve field stimulation (PNFS) is a promising modality for treatment of intractable facial pain. However, evidence is sparse. We are therefore presenting our experience with this technique in a small patient cohort. Methods: Records of 10 patients (five men, five women) with intractable facial pain who underwent implantation of one or several subcutaneous electrodes for trigeminal nerve field stimulation were retrospectively analyzed. Patients’ data, including pain location, etiology, duration, previous treatments, long-term effects and complications, were evaluated. Results: Four patients suffered from recurrent classical trigeminal neuralgia, one had classical trigeminal neuralgia and was medically unfit for microvascular decompression. Two patients suffered from trigeminal neuropathy attributed to multiple sclerosis, one from post-herpetic neuropathy, one from trigeminal neuropathy following radiation therapy and one from persistent idiopathic facial pain. Average patient age was 74.2 years (range 57–87), and average symptom duration was 10.6 years (range 2–17). Eight patients proceeded to implantation after successful trial. Average follow-up after implantation was 11.3 months (range 5–28). Using the visual analog scale, average pain intensity was 9.3 (range 7–10) preoperatively and 0.75 (range 0–3) postoperatively. Six patients reported absence of pain with stimulation; two had only slight constant pain without attacks. Conclusion: PNFS may be an effective treatment for refractory facial pain and yields high patient satisfaction.
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Rode, Frederik. "Pharmacological testing in the spared nerve injury model of neuropathic pain /." Cph. : The Danish University of Pharmaceutical Sciences, Department of Pharmacology, 2005. http://www.dfuni.dk/index.php/Frederik_Rode/1938/0/.
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Evans, Laura Jane. "Peripheral changes in NGF in a spared fibre model of neuropathic pain." Thesis, University of Sheffield, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.574620.
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The experiments described in this thesis have investigated the role of nerve growth factor (NGF) acting on spared nerve fibres in the pathophysiology of neuropathic pain, caused by a partial nerve injury of the mental nerve, a branch of the trigeminal nerve that innervates the skin and mucosa of the lower lip. The experiments have tested the hypothesis that an over-supply of NGF acts on a reduced population of mental nerve fibres and causes phenotypic changes in the population that could underlie symptoms of neuropathic pain. A behavioural testing protocol was developed to investigate the presence and severity of neuropathic pain to thermal and mechanical stimuli after a chronic constriction injury of the mental nerve. The concentration of NGF in the skin of the lower lip was investigated with an ELISA (enzyme-linked immunosorbant assay) and the neurochemistry of the remaining sensory nerve fibres that innervate the skin of the lip was investigated quantitatively using triple-labelling immunofluorescence. Experiments to determine the time-course of the development of neuropathic pain were conducted initially, and when symptoms were maximal (11, 14 and 21 days post-operatively) further studies on NGF concentration and neurochemical phenotype were performed. A chronic constriction injury of the mental nerve produced cold hyperalgesia in the ipsilateral lower lip 1I days post-injury, although at this time the NGF concentration in the lower lip did not differ between ipsilateral and contralateral sides (ipsilateral = 45±6(SEM) pg/mg, contralateral = 47±7 pg/mg). NGF concentration was significantly increased ipsilaterally compared to contra laterally 14 days post-operatively (ipsilateral = 111±23 pg/mg, contralateral = 69± 13 pg/mg), however, at this time-point there was no behavioural evidence of neuropathic pain. By 21 days post-injury, NGF concentration both ipsilaterally and contralaterally was elevated compared to data for 11 days but there was no significant difference between sides (ipsilateral = 181±31 pg/rng, contralateral = 205±30 pg/rng) and there was also no behavioural evidence of neuropathic pain. Quantitative immunohistochemistry of samples 21 days post-injury showed a significant increase on the ipsilateral side (ipsilateral = 85± 17%, contralateral = 46±5%) in the proportion of nerve fibres that were double-labelled for trkA (the high-affinity NGF receptor) and Calcitonin gene-related peptide (CGRP) and this change was absent at 11 and 14 days post-injury. The data from these investigations suggest that cold hyperalgesia following partial injury to the mental nerve is not induced from an altered concentration of NGF in the skin and that a different mechanism may cause this symptom. Transiently increased NGF on the ipsilateral side may have caused an increased proportion of CGRP immunoreactive fibres in the trkA population and this difference in innervation pattern coincided temporally with mechanical nociceptive thresholds on the ipsilateral side that were lower than those on the contralateral side (due to a lack of habituation which occurred on the contralateral side of chronic constriction injuries and on both sides of sham operated animals).
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Ntogwa, Mpumelelo. "Mechanisms of HIV-induced peripheral neuropathic pain by focusing on Schwann cell-macrophage interaction." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263602.
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XIE, WENRUI. "BLOCKADE OF ECTOPIC ACTIVITY AT THE INITIAL STAGE OF PERIPHERAL NERVE INJURY PREVENTS NEUROPATHIC PAIN." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1057691866.
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Stötzner, Philip [Verfasser]. "Opioids in neuropathic pain - the role of potassium channels in peripheral sensory neurons / Philip Stötzner." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1160515018/34.
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Durrenberger, Pascal F. "Peripheral and central mechanisms in chronic human inflammatory and neuropathic pain and associated animal models." Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/11344.
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Evangelista, Afrânio Ferreira. "Avaliação do efeito do transplante de células-tronco mesenquimais derivadas de medula óssea em modelo murino de neuropatia periférica diabética." Centro de Pesquisas Gonçalo Moniz, 2014. https://www.arca.fiocruz.br/handle/icict/9646.
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Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
O diabetes é uma doença de alta prevalência que, frequentemente, induz o comprometimento do sistema nervoso periférico. Na neuropatia diabética periférica, os sintomas mais encontrados são os sensitivos, no qual a dor neuropática, condição crônica caracterizada por alodinia e hiperalgesia, é a mais debilitante. Esta, prejudica a qualidade de vida do paciente, sendo muitas vezes não responsiva aos métodos farmacológicos convencionais de tratamento. Diante desse panorama, o desenvolvimento de novas abordagens terapêuticas que possuam ação efetiva neste tipo de dor é de grande relevância. O uso da terapia celular no tratamento de lesões do sistema nervoso tem demonstrado resultados promissores e o potencial terapêutico de células-tronco na neuropatia experimental tem sido proposto. Neste estudo, avaliou-se o efeito de células-tronco mesenquimais derivadas da medula óssea (CMsMO) na neuropatia diabética periférica estabelecida em modelo experimental de diabetes induzido por estreptozotocina (ETZ). Quatro semanas após a indução do modelo por ETZ (80 mg/kg; ip; 3 dias consecutivos), os animais receberam uma administração endovenosa de CMsMO (1 x 106) ou veículo. O tratamento com gabapentina (30 mg/kg; v.o. a cada 12 horas durante seis dias consecutivos) foi usado como padrão ouro. Os limiares nociceptivos térmico e mecânico foram avaliados durante todo o período experimental (90 dias), pelos métodos de hargreaves e von Frey. A avaliação da função motora foi realizada pelo teste de rota-rod. Em diferentes tempos e para todos os grupos experimentais, foram realizadas coletas de segmentos da medula espinal (L4-L5) para dosagem de citocinas por ELISA e segmentos do nervo isquiático foram também coletados para avaliação de alterações morfológicas por microscopia óptica e eletrônica de transmissão. Os dados comportamentais demonstraram que o tratamento com CMsMO reduziu a mecanoalodinia e a hipoalgesia térmica, levando os limiares nociceptivos de animais neuropáticos a níveis similares aos de animais não neuropáticos. Do mesmo modo, a administração de CMsMO normalizou a função motora dos animais neuropáticos. Dados de microscopia mostraram que animais neuropáticos apresentaram atrofia axonal, redução do número de fibras mielínicas e aparente redução do numero de fibras amielínicas no nervo isquiático. Animais neuropáticos tratados com CMsMO tiveram menor ocorrência de atrofia axonal e não apresentaram redução do numero de fibras mielínicas ou amielínicas, em relação aos neuropáticos tratados com salina. Além disso, animais neuropáticos tratados com CMsMO apresentaram menores níveis espinais de IL-1β e TNF-α, e maiores de IL-10 e TGF-β, em relação aos animais neuropáticos não tratados. Esse conjunto de resultados indica que CMsMO produzem efeito antinociceptivo duradouro na neuropatia diabética, seguido de modificações no padrão fisiopatológico da doença, o que aponta a terapia celular como uma interessante alternativa para o controle da neuropatia diabética periférica dolorosa.
Diabetes is a highly prevalent disease which frequently compromises the peripheral nervous system. In peripheral diabetic neuropathy, the most frequent symptoms are sensitive, in which the neuropathic pain, chronic condition characterized by allodynia and hyperalgesia, is the most debilitating. Neuropathic pain affects the quality of patients’ lives, and is often not responsive to pharmacological conventional treatment methods. Against this background, the development of new therapeutic approaches that have an effective action in this type of pain is of great importance. The use of cell therapy in the treatment of lesions in the nervous system has shown promising results and the therapeutic potential of stem cells in experimental neuropathy has been proposed. In this study, we evaluated the effect of mesenchymal stem cells derived from bone marrow (CMsMO) in peripheral diabetic neuropathy established in experimental model of streptozotocin (STZ) induced diabetes in mice. Four weeks after the induction of the model by administration of STZ (80 mg/kg, ip; 3 days) the animals received an CMsMO by intravenous administration (1x106) or vehicle. The treatment with gabapentin (30 mg/kg, orally every 12 hours for six days) was used as the gold standard. The thermal and mechanical nociceptive thresholds were assessed throughout the entire experimental period (90 days), using Hargreaves and von Frey methods, respectively. Motor function evaluation of was conducted using the rotarod test. At different times, were analyzes conducted in spinal cord segments (L4-L5) to determine cytokines profile by ELISA. Sciatic nerve segments were also collected for evaluation of morphological changes by optical and electron transmission microscopy. According to the behavioral data, the CMsMO treatment reduced the mecanoalodinia and the thermal hypoalgesia, leading nociceptive thresholds of neuropathic animals to levels similar to those of non-neuropathic animals. Similarly, CMsMO administration normalized motor function of neuropathic animals. Microscopy data demonstrated that neuropathic animals had axonal atrophy and an apparent decrease of the number of myelinated fibers as well a reduction in the number of unmyelinated fibers in the sciatic nerve, but neuropathic animals treated with CMsMO had a lower incidence of axonal atrophy, showed no decrease in the number of myelinated fibers and no apparent decrease in the amount of unmyelinated fibers in relation to neuropathics treated with saline. Furthermore, neuropathic animals treated with CMsMO presented lower levels of spinal IL-1β and higher levels of TNF-α, and IL-10 and TGF-β compared to neuropathic animals that received saline. These data indicate that CMsMO produces a lasting analgesic effect in diabetic neuropathy, followed by changes in the pathophysiological disease pattern, which indicates cell therapy as an interesting alternative for the control of painful peripheral diabetic neuropathy.
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Ramnarine, Sabrina. "Translational approach to the characterisation, early identification and treatment of chemotherapy-induced peripheral neuropathy." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28888.
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Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity with significant sequelae impacting prognosis and quality of life. The natural history and pathophysiological mechanisms of CIPN are unclear. Equally, the lack of systematic approach to diagnosis and assessments contribute to difficulty identifying at risk patients with implications on symptom burden. Effective management of CIPN is also difficult due to limited treatment options. To try and address this challenging clinical problem, this thesis aimed to adopt a translational approach to: 1) characterisation and early identification of the development of CIPN in cancer patients receiving neurotoxic chemotherapy and 2) explore topical treatment options in patients with chronic peripheral neuropathic pain. Methodology In the CIPN study, a mixed cohort of colorectal, gynaecological and lung cancer patients receiving neurotoxic chemotherapy (platinum agents and taxanes) were assessed prospectively, at baseline (prior to initiating chemotherapy), during cycles (every 3 weeks) and post-treatment (every 3 months) for up to 12 months (cumulative 261 assessments). Comprehensive longitudinal clinical characterisation consisted of the integration of quantitative sensory testing (QST), objective measure of function (grooved pegboard test), patient-reported outcomes and in vivo confocal microscopy to provide insight into the clinical course and potential psychophysical biomarkers of CIPN during and after chemotherapy. In the pilot intervention study, patients with chronic, complex cancer treatment related peripheral neuropathic pain received a single application of high concentration 8% capsaicin patch. Assessments conducted at baseline, 4 weeks and 12 weeks included patient-reported outcomes and QST with an exploratory application of in vivo confocal microscopy in a case. Results In the CIPN study, 33 patients when compared to 33 age and gender matched healthy controls displayed thermal hyperalgesia, sensorimotor impairment and increased resting heart rate prior to initiating neurotoxic chemotherapy. Characterisation of somato-sensory profile demonstrated dysfunction of the various types of primary afferent nerves (Aβ, Aδ and C). Assessing the change over time from baseline to during cycles and post-treatment follow up, revealed signs and symptoms as early as cycle 2 with an increase in the later cycles and 3 months post-treatment follow up. A greater burden was observed at 12 months in comparison to baseline. Significant changes were observed in QST parameters indicating both small and large fibre deficits. Interesting associations were observed for example with tactile deficits in the upper and lower limb and patient-reported outcomes. The repeated measures model provided an opportunity to distil the relationship between subjective and objective measures of CIPN. The subclinical findings at baseline however did not translate to obvious predictors of CIPN development. The exploratory use of in vivo confocal microscopy (45 healthy controls, 9 patients) demonstrated correlation with current assessment tools (QST). Analysis from the pilot intervention study of 20 patients revealed clinically significant improvement in pain in a subset at 4 and 12 weeks post-treatment. Conclusion Overall the combination of subjective and objective measures utilised in the prospective characterisation of this mixed cohort of cancer patients provided a useful paradigm for qualifying and quantifying the trajectory of CIPN related peripheral nerve damage and symptom burden with additional contribution from the novel in vivo confocal microscopy work. In capturing the varied spectrum of phenotypes, this approach may provide insight into the complexities of the underlying neurobiological mechanisms. The baseline subclinical sensory, motor and autonomic nerve dysfunction implicate a cancer-mediated process possibly contributing to CIPN. Although the preliminary investigation of baseline predictors of CIPN was inconclusive, thermal pain threshold warrant further investigation. These findings highlight the need to further address prediction and risk stratification in larger studies. The exploratory intervention study suggests that patients with chronic neuropathic pain may receive some benefit in pain severity, function and mood with effect continuing at 12 weeks post-treatment. This research warrants further investigation in larger cohorts.
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Font, Ingles Joan. "Deciphering the role of peripheral and central nervous system metabotropic glutamate receptors in neuropathic pain with photoactivable ligands." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/404123.
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Pain is one of the main medical problems that in several cases results into a chronic disease with limited effective treatment, thus the discovery of new drugs to fight against constitutes a big challenge nowadays.
Metabotropic glutamate receptors (mGluRs) are widely distributed along the pain neuraxis and modulate pain transmission at different anatomical levels. Hence, subtype-selective mGlu receptors ligands are considered a promising candidate drugs for the treatment of acute, chronic and neuropathic pain. Accordingly, selective negative allosteric modulators (NAMs) of mGlu1 and mGlu5 receptors, and agonists or positive allosteric modulators (PAMs) of mGlu2 or mGlu4 receptors have consistently been shown to display analgesic activity in experimental animal models of chronic pain. However the systemic use may be limited by mechanism-related adverse effects. An effective strategy to overcome this limitation would consist of developing inactive photosensitive mGlu5, mGlu1 and mGlu4 receptors-based drugs, which may thereafter be activated by light administration with spatiotemporal control exclusively in the located area where pain takes place, or even in brain regions critically involved in pain control.
Two main optopharmacology approaches were used in this thesis for the photo delivering such as photoswitchable compounds (photoisomerisation) or caged compounds (photolysis).
On the one hand, photoswitchable compounds are molecules (normally azobenzenes) that coexist in two possible conformations (trans or cis) being the trans conformation the isomer thermodynamically stable. Moreover, these azo groups are bioisosteres of several groups such as amides, acetylenes or triazole. Interestingly, the addition of an azo group promotes the control of protein function, which had been demonstrated in a previous work with photoswitchable compounds as Alloswitch-1 or Optogluram. Unfortunately, their trans isomer provides the biological activity, meaning the compound is active in the stable disposition and we could just inactivate them upon irradiation. Due this reason, the needs to find a photoswitchable compound active in cis disposition are more interesting in a therapeutic point of view.
On the other hand, caged compounds consist in known drugs modifying by a single covalent bond, to mask the biological activity and release them selectively under light irradiation. The main issue presented by these compounds are a losing of control after irradiation.
Several photochromic compounds targeting the mentioned mGluRs were designed and synthesized in the present thesis, evaluating these compounds in several fields as photochemistry, pharmacology and even in in-vivo experiments.El dolor és un dels principals problemes de salut, que en diversos casos es tradueix en una malaltia crònica amb un tractament efectiu limitat, per tant, el descobriment de nous fàrmacs per lluitar-hi, constitueix en molts casos, un gran repte avui dia. Els receptors metabotròpics del glutamat (mGluRs) estan àmpliament distribuïts al llarg del sistema nerviós central i perifèric, i modulen la transmissió del dolor en diferents nivells anatòmics. Els diferents lligands per a la modulació dels diferents subtipus de mGlus, es consideren uns fàrmacs prometedors per al tractament del dolor agut, crònic i neuropàtic. Recentment, s'ha demostrat que els moduladors al·lostèrics negatius (NAM) selectius en mGlu1 o mGlu5, i els agonistes o moduladors al·lostèrics positius (PAM) de mGlu2 o mGlu4 mostren activitat analgèsica en models animals de dolor crònic. No obstant això, l'ús sistèmic pot ser limitat pels efectes adversos. Una estratègia efectiva per superar aquesta limitació consisteix en el desenvolupament de lligands inactius fotosensibles per els receptors mGlu5, mGlu1 i mGlu4, per ser activats després amb l’aplicació de llum amb un control espai-temporal exclusivament en l’àrea on es localitza el dolor o inclòs en regions del cervell involucrats en el control del dolor. Existeixen principalment dos tipus de aproximacions en optofarmacologia, i que han estat utilitzat en la present tesis, els compostos fotocommutables (fotoisomerització) o compostos gàbia (fotòlisis). D’una banda, els compostos fotocommutables són molècules (normalment azobenzens) que coexisteixen en dos conformacions possibles (trans o cis), sent la conformació trans el isòmer termodinàmicament estable. A més, els grups azo són bioisòsters de diferents grups funcionals alguns com amides, acetilens o triazols. Amb l’adició d’aquest grup obtenim un control sobre la funció de la proteïna, demostrat en anteriors treballs realitzats per el grup. Desafortunadament, el isòmer trans d’ambdues molècules era el conformació biològicament activa, significant que el compost era actiu en la seva conformació estable i nomes es podia desactivar mitjançant llum. Per aquesta raó, el descobriment de nous compostos fotocommutables actius en disposició cis són més interessants des de un punt de vista terapèutic. D’altre banda, els compostos gàbia consisteixen en la modificació de compostos actius per un enllaç covalent, que emmascara la seva activitat biològica, alliberant-ne el compost actiu sota irradiació.
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Zandonai, Alexandra Paola. "Adaptação transcultural e validação do instrumento Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT) para o Brasil." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/22/22132/tde-01022016-162439/.
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Introdução: A Neuropatia Periférica Induzida pela Quimioterapia (NPIQ) é um efeito adverso comum e debilitante ocasionado pela infusão de agentes quimioterápicos neurotóxicos como os taxanos, as platinas, alcalóides da vinca, bortezomibe e talidomida. A administração destas medicações aumentam a sobrevida do paciente, porém, aproximadamente, 30% a 40% desenvolvem NPIQ, o que afeta negativamente o tratamento planejado e a qualidade de vida ao interferir nas atividades diárias do paciente. A NPIQ manifesta-se com sintomas sensitivos (parestesia, disestesia, dor entre outros), motores (fraqueza, alterações na marcha e no equilíbrio, dificuldade nas habilidades motoras finas e outros) e neurovegetativos (constipação, retenção urinária, disfunção sexual e alterações na pressão sanguínea). Até o momento não foi concebido um instrumento que avalie a dor neuropática na NPIQ e, além disso, não há instrumento validado com essa finalidade no Brasil. Objetivos: Realizar a tradução e adaptação transcultural do instrumento Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT) para a língua portuguesa do Brasil e testar as propriedades psicométricas da versão adaptada em uma amostra de pacientes oncológicos, que apresentavam NPIQ. Métodos: Trata-se de um estudo metodológico com coleta de dados transversal. Para o processo de tradução e adaptação do instrumento, adotou-se o referencial teórico metodológico proposto por Beaton e colaboradores (2000). A coleta de dados ocorreu em dois hospitais referência no tratamento oncológico da cidade de São Paulo. Resultados: Obteve-se uma amostra de 245 participantes, sendo que, 135 (55,1%) apresentavam neoplasia maligna de intestino, 162 (66,1%) usavam um quimioterápico da classe análogos da platina, 125 (51%) manifestavam dormência nas mãos com gravidade média de 6,71 e angústia média de 7,0 (numa escala de 0-10), impactou negativamente nas Atividades de Vida Diária (AVD) como a prática de exercícios, o trabalho e atividades de lazer. Para testar a validade de construto convergente fez-se uma correlação de Spearmam da versão adaptada do CIPNAT com os instrumento NPSI e DN4 e, obteve-se uma moderada correlação. Não foi possível atingir a validade discriminante. A análise fatorial exploratória com rotação varimax identificou dois fatores, sendo estes, sintomas sensitivos e sintomas motores. Em relação a confiabilidade, alcançou-se um alfa de Cronbach de 0,87, considerado satisfatório. O teste-reteste demonstrou uma forte correlação entre a primeira e segunda avaliação pelo CIPNAT, sendo considerado estável. Conclusão: A análise psicométrica do CIPNAT foi adequada. Desta forma, estará disponível um instrumento válido e confiável que rastreia, caracteriza, avalia e mensura a NPIQ e seu impacto nas AVDs para que a enfermagem oncológica promova uma assistência segura e com qualidadeBackground: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common and debilitating adverse effects caused by the infusion of neurotoxic chemotherapeutics such as taxanes, platines, vinca alkaloids, bortezomib and thalidomide. The administration of these medications increase patient survival, however, approximately 30% to 40% develop CIPN, which negatively affects the planned treatment and the quality of life by interfering with daily activities of the patient. The CIPN manifests itself with sensory symptoms (paresthesia, dysesthesia, pain and others), motors (weakness, changes in gait and balance, difficulty with fine motor skills and others) and neurovegetative (constipation, urinary retention, sexual dysfunction and changes in blood pressure). So far, it has not been a tool designed to evaluate the neuropathic pain in CIPN and furthermore, there is no validated instrument for this purpose in Brazil. Aims: To perform the translation and cultural adaptation of Chemotherapy- Induced Peripheral Neuropathy Assessment Tool instrument (CIPNAT) into Portuguese of Brazil and test the psychometric properties of the adapted version in a sample of cancer patients with CIPN. Methods: This is a methodological study with cross data collection. For the process of translation and adaptation of the instrument, it was adopted the methodological theoretical framework proposed by Beaton et al (2000). Data collection occurred in two referral hospitals in the oncological treatment of São Paulo. Results: There was obtained a sample of 245 participants, and that 135 (55.1%) had colorectal neoplasm, 162 (66.1%) used a platinum chemotherapeutic agent, 125 (51%) manifested numbness in the hands with medium gravity of 6.71 and average distress of 7.0 (on a scale of 0-10), impacted negatively on the activities of Daily Living (ADLs) such as exercise, work and leisure activities. To test the convergent validity has made a Spearman\' correlation of the adapted version of CIPNAT with NPSI and DN4 instrument and, was obtained a moderate correlation. Could not achieve the discriminant validity. Exploratory factor analysis with varimax rotation identified two factors, which are, sensory symptoms and motor symptoms. Regarding reliability, it was reached a Cronbach\'s alpha of 0.87, satisfactory. The test-retest showed a strong correlation between the first and second evaluation by CIPNAT and is considered stable. Conclusion: The psychometric analysis of CIPNAT was adequate. Thus, it will be available a valid and reliable instrument that tracks, features, evaluates and measures the CIPN and its impact on ADL for the oncology nursing promotes safe and quality care
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Barros, Filho Marcos de [Verfasser], and Guilherme [Akademischer Betreuer] Lepski. "Assessment of chronic peripheral localized neuropathic pain during stimulation of the dorsal root ganglion using laser-evoked potentials / Marcos de Barros Filho ; Betreuer: Guilherme Lepski." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1199615137/34.
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Ng, Wing Tin Sophie. "Douleur et caractérisation neurophysiologique de l'atteinte des petites fibres dans les neuropathies périphériques." Thesis, Paris Est, 2013. http://www.theses.fr/2013PEST0117.
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L'objectif de notre travail était dans un premier temps d'étudier les liens entre l'altération des fibres nerveuses de petit diamètre et la présence de douleurs chez des patients ayant une neuropathie périphérique. Notre deuxième objectif était d'évaluer la pertinence de certaines techniques neurophysiologiques pour mettre en évidence l'atteinte de ces petites fibres nerveuses. Notre première étude réalisée sur une large cohorte de patients présentant divers types de neuropathie a montré, grâce à une étude quantifiée de la sensibilité, qu'il n'y avait pas de corrélation entre la perte ou perte de fonction des fibres nerveuses de petit diamètre et la présence de douleurs. Ceci a été confirmé par notre deuxième étude portant sur une population plus homogène de patients ayant une neuropathie amyloïde familiale et étudiés avec une batterie neurophysiologique plus large. Ainsi, les douleurs neuropathiques des patients présentant une neuropathie périphérique sont probablement dues à la combinaison de facteurs d'hyperexcitabilité périphérique et de sensibilisation centrale et non directement liée à la perte en petites fibres. Il reste cependant pertinent de développer des techniques objectives d'exploration de ces petites fibres notamment dans un but de diagnostic clinique. Notre troisième étude a montré que certaines méthodes neurophysiologiques étaient particulièrement sensibles dans ce cadre en prenant pour exemple la détection d'anomalies précoces d'atteinte des petites fibres au cours de la neuropathie amyloïde familiale. Une batterie de tests comprenant l'enregistrement des potentiels évoqués laser, la mesure du seuil de détection du chaud et de la conductance cutanée, s'est avérée être la combinaison la plus pertinente, comme l'a montré notre quatrième étude sur une grande cohorte de patients susceptibles de présenter une neuropathie des petites fibresThe aim of our work was initially to study the relationship between alterations in small diameter nerve fibers and the presence of pain in patients with peripheral neuropathy. Our second objective was to assess the relevance of some neurophysiological tests to characterize these alterations in small nerve fibers. Our first study of a large cohort of patients with various types of neuropathy showed, using quantitative sensory testing, that there was no correlation between the loss or loss of function of small nerve fibers and the presence of pain. This was confirmed by our second study focused on a more homogeneous population of patients with familial amyloid neuropathy and studied with a larger neurophysiological battery. Thus, neuropathic pain in patients with peripheral neuropathy is probably due to a combination of factors of peripheral hyperexcitability and central sensitization and not directly related to the loss of small nerve fibers. However, it remains relevant to develop techniques of objective investigation of these small nerve fibers for a purpose of clinical diagnosis. Our third study showed that some neurophysiological methods were particularly sensitive in this context, taking the example of the detection of early alteration of small nerve fibers in familial amyloid neuropathy. A battery of tests, including laser evoked potential recording, warm detection threshold and electrochemical skin conductance measurement, proved to be the most appropriate combination for this diagnostic purpose, as shown by our fourth study on a large cohort of patients likely to have a small fiber neuropathy
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Bouchenaki, Hichem. "Evaluation de l'effet de molécules candidates dans des modèles murins de neuropathies périphériques induites par la chimiothérapie anticancéreuse." Thesis, Limoges, 2020. http://www.theses.fr/2020LIMO0035.
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Les neuropathies périphériques induites par la chimiothérapie (NPIC) sont un effet indésirable commun des agents anticancéreux. Les symptômes des NPIC sont principalement sensitifs : douleurs, fourmillements, sensations d’engourdissement, altérations de la sensibilité thermique et mécanique. La symptomatologie des NPIC est associée à une forte altération de la qualité de vie des patients, et peut dans certains cas conduire à une diminution des doses et des cycles de chimiothérapie, voire à un arrêt du traitement. La prise en charge actuelle des NPIC repose principalement sur l’utilisation de molécules recommandées dans le traitement des douleurs neuropathiques, et dont l’efficacité reste très modeste. L’intérêt de l’utilisation de modulateurs du système rénine-angiotensine, et plus principalement de la stimulation des récepteurs AT2 à l’angiotensine II, a été précédemment mis en évidence au sein du laboratoire, dans un modèle murin de neuropathie induite par la vincristine. Au cours du présent travail, nous avons développé un modèle de douleur neuropathique induite par l’oxaliplatine (OXP), un agent anticancéreux de la famille des sels de platine. Nous avons mis en évidence un effet bénéfique du ramipril, un inhibiteur de l’enzyme de conversion de l’angiotensine I en angiotensine II, dans la douleur neuropathique induite par l’OXP. Nous avons également mis en évidence l’effet préventif du ramipril et du candésartan, un antagoniste des récepteurs AT1 à l’angiotensine II, contre l’allodynie mécanique induite par le paclitaxel (PTX), un agent anticancéreux de la famille des taxanes. L’effet préventif du candésartan contre l’hypersensibilité mécanique induite par le PTX est médiée par la stimulation indirecte des récepteurs AT2 à l’angiotensine II. Paradoxalement, la stimulation directe ou indirecte des récepteurs AT2 n’a pas permis de prévenir la douleur neuropathique induite par l’OXP. Ces travaux mettent donc en lumière la nécessité du développement d’un traitement des NPIC adapté à la physiopathologie de chaque agent anticancéreuxChemotherapy-induced peripheral neuropathies (CIPN) are a common side effets of chemotherapeuticagents. CIPN symptoms are mainly sensitive: pain, tingling, numbness or alterations of thermal andtactile sensitivity. CIPN symptomatology is associated to decreased patient quality of life and can leadto decreased chemotherapy doses and cycles, or even therapy cessation. Current CIPN managementconsists in the administration of medications recommended in the treatment of neuropathic pain, withvery low efficacy. The benefit of using renin-angiotensin system modulators has been previouslydemonstrated in our lab, in a murine model of vincristine-induced peripheral neuropathy. In thepresent work, we developed a new model of neuropathic pain, induced by oxaliplatin (OXP), achemotherapeutic agent belonging to the platinum family. We showed that an angiotensin-convertingenzyme inhibitor, ramipril, was able to alleviate OXP-induced neuropathic pain. We also showed thatboth ramipril and candesartan, an angiotensin II AT1 receptor antagonist, were able to prevent tactileallodynia induced by paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane family. Thepreventive effect of candesartan against PTX-induced tactile allodynia is mediated by the indirectstimulation of angiotensin II AT2 receptors. Paradoxically, the direct or indirect AT2 receptorsstimulation did not prevent OXP-induced neuropathic pain, thus highlighting the necessity to adapt thepotential CIPN treatments to each chemotherapeutic agent physiopathology
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Eriksson, Malin Elisabeth Viktoria. "Sleep in patients with painful diabetic peripheral neuropathy : impact of pain, glucose and pharmacological intervention." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/804058/.
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Matthews, Laura Clare. "Chronic pain associated with diabetic peripheral neuropathy : impact on quality of life and cognitive function." Thesis, University of Surrey, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543918.
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Seretny, Marta. "Investigating Chemotherapy Induced Peripheral Neuropathy (CIPN) and its treatment, using functional Magnetic Resonance Imaging (fMRI)." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/23611.
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Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating neuropathy caused by commonly used chemotherapeutics. Clinically, the problem of CIPN is compounded by difficulties with diagnosis and limited treatment options. The pathophysiology of CIPN remains elusive, with current mechanistic postulates focused mainly on the peripheral nervous system. However, animal and human models of non-CIPN neuropathic conditions have shown the brain to be central to the development and maintenance of painful neuropathy. Moreover, evidence suggests that aberrant activity in key regions of the brain and brainstem could denote individual vulnerability for chronic pain states. The impact of the brain on CIPN development is unknown. Assessment of drug efficacy using brain imaging can provide sensitive readouts and is increasingly used in clinical trials. Aims: Firstly, to prospectively explore the structure and function of the brain in cancer patients prior to chemotherapy administration, using functional magnetic resonance imaging (fMRI), in order to determine whether baseline differences exist between patients who progress to CIPN as compared to those who do not. Secondly, to develop a pilot study using fMRI to investigate a topical treatment for CIPN, in order to assess the feasibility of setting up a study with this kind of design. Methods: To address the first aim of this thesis a prospective cohort study (the CIPN fMRI Study) was developed. Cancer patients scheduled to receive neurotoxic chemotherapy treatment including oxaliplatin, carboplatin, carbotaxol, or cisplatin, were recruited from three NHS trusts in Scotland, to undergo a high resolution (3 tesla) functional MRI scan, at a single time point prior to commencement of chemotherapy. During the scan structural, resting state and functional data were collected. Functional data involved the presentation of punctate stimuli (using a 256mN von Frey filament), above the patients’ right medial malleolus. While receiving the punctate stimuli, patients viewed images that had neutral or positive emotional content or a baseline coloured image with no content. Sample size was based on previously successful pain fMRI studies and pragmatic estimates. Acute CIPN was defined clinically by common toxicity criteria as necessitating a chemotherapy dose reduction or cessation. Data were analysed using FMRIB’s Software Library (FSL) version 5, 2015. Standard data pre-processing (brain extraction, registration, B0 unwarping, motion correction, and denosiing with FIX) was carried out. Structural analysis was conducted using FIRST. Resting state analysis utilised FSL’s MELODIC tool, and a non-parametric group comparison was made following a dual regression approach. FEAT was used for both first and second level functional analyses. Group comparisons were made using a mixed effects analysis (z threshold 2·3 and 2, regions considered significant at p < 0·05, cluster corrected). The group was split by sex to explore known sex differences in pain processing. To address the second aim of this thesis, a pilot fMRI randomised controlled trial (MINT3 Study) was designed. Approvals from ethics and research and development were sought and obtained. Data collection forms were developed. An fMRI experiment was proposed and a single pilot scan was conducted and analysed. Results: 30 patients were recruited for the CIPN fMRI study (mean age 60·4 years, 95% Confidence Interval: 57.4-63.4, 17 women). Two patients had lung cancer, nine had gynecological malignancies and 18 had colorectal cancer. 17 patients developed acute CIPN. Structural analysis showed that patients who developed CIPN had a smaller volume of the Nucleus Accumbens (NAc). Resting state analysis did not show clear differences between those who developed CIPN and those who did not. Finally, functional analysis showed that patients who did not develop CIPN had greater activation in the superior frontal gyrus when viewing positive emotional images as compared to those who did progress to CIPN. Region of interest analysis showed that female patients who developed CIPN had greater activity in their mesencephalic pontine reticular formation (MPRF). Male patients who progressed to CIPN had decreased activity in their thalamus. Feasability of the MINT3 study set up and fMRI paradigm was assessed. Interpretation Differences in brain structure and function are evident between patients who developed CIPN and those who did not. Crucially, the regions identified, in particular the NAc, have been postulated to denote a vulnerability for progression to pain states. Although the findings need further confirmation they suggest a paradigm shift in terms of CIPN as a clinical problem. Specifically, it appears that certain individuals can be considered as having increased risk of CIPN development prior to chemotherapy administration. This risk relates to the baseline structure, and function of their brains. Finally, the set up of the MINT3 fMRI study showed that this kind of study design is acceptable in terms of ethical and R&D approvals and a single healthy volunteer pilot.
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du, Plessis Ronél. "Effect of an exercise training programme on muscular strength, ankle mobility, balance and gait patterns in patients with diabetic peripheral neuropathy in the lower legs." University of the Western Cape, 2021. http://hdl.handle.net/11394/8049.
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>Magister Scientiae - MScBackground: Patients who suffer from diabetic peripheral neuropathy in the leg experience a greater risk of developing gait deviations due to a decrease in strength of the lower extremities, especially the tibialis anterior and triceps surea muscle groups. Aim: The aim of the study was to determine the effect of an exercise training programme on blood pressure, fasting blood glucose, muscle strength, range of motion, balance and gait pattern deviations in patients with diabetic neuropathies. Methods: A total of fourteen participants, who had been diagnosed with diabetic peripheral neuropathy or nocturnal allodynia in either one or both extremities, were asked to participate in this study. Participants were purposively selected from two private Podiatry practices based on their signs and symptoms of diabetic neuropathy, age, gender and doctor’s clearance to participate in any form of physical activity. Dependent variables included isometric strength of the muscles surrounding the hip, knee and ankle, the range of motion of the ankle in plantarflexion and dorsiflexion using goniometry, an assessment of balance using the stork stand test, and a gait pattern analysis, using the modified Tinetti Gait pattern Assessment Scale. Study design: The study was a single-blinded, pre-test and post-test experimental study design using a quantitative approach. Intervention: The researcher (a registered biokineticist) developed a scientifically-based exercise intervention programme to specifically target the entire kinetic chain, and to reduce fall risks, improve quality of life and to assist in developing a standard protocol for patients with DPN. The intervention programme consisted of a combination of ankle, hip and knee rehabilitation, including gait pattern specific rehabilitation. The intervention took place 2-3 times a week for 45 minutes per session and was divided in four categories: Range of motion exercises, strengthening exercises, balance and proprioception and gait pattern training exercises. Results: The Mann-Whitney and Wilcoxon Sign Rank Tests were used to evaluate the differences in dependent variables from pre- to post-intervention. The level of significance was set at p<0.05. An increase in range of motion only in the left ankle dorsiflexion were observed and an increase in balance time for the left leg were observed in the intervention group after a 10-week follow up assessment. Clinical significance was observed in the intervention group, post-intervention, with a decrease in systolic (-9.09%) and diastolic blood pressure (-13.89%) and a decrease in blood glucose levels (-17.89%), however, an increase in these variables was observed in the control group post-intervention. An increase in plantarflexion, 8% (left) and 8% (right) and dorsiflexion 5.26% (left) and an 11.11% (right) increase in range of motion for both left and right ankles, and balance time for both legs, 200% (left) and 159% (right) was observed in the intervention group post-intervention. Although the muscular strength variables showed a mix of an increase and decrease in strength post-intervention in the intervention group, however a clinically significant decreased amount was observed in the control group post-intervention for the majority of muscular strength variables. Conclusions: Although not many findings of this study are statistically significant, clinical significance were observed with most of the variables of this study. The findings of this study can assist future researchers in the development of exercise interventions for patients who suffers from DPN.
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Koyanagi, Madoka. "Investigation of the mechanisms of taxane-induced peripheral neuropathy focusing on Schwann cell and search for novel therapies by drug repositioning." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263608.
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Mota, Clarissa Maria Dias. "Atividade da proteína quinase dependente de RNA (PKR) no sistema nociceptivo em um modelo experimental de neuropatia periférica de origem viral." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-21072016-143055/.
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A proteína quinase dependente de RNA (PKR) é uma molécula sentinela ativada em situações de estresse celular, incluindo infecções virais. A ativação de PKR por meio de sua fosforilação aciona cascatas de sinalização intracelular envolvidas em respostas inflamatórias e inibição da síntese protéica. Dados prévios do nosso laboratório sugerem que PKR está envolvida na hiperalgesia térmica de origem inflamatória. No presente estudo, foi investigado o papel da PKR na hiperalgesia térmica induzida pelo vírus da herpes simples tipo 1 (HSV1), durante as fases herpética e pós-herpética, combinando métodos comportamentais, genéticos, farmacológicos e moleculares. Camundongos C57bl/6, PKR+/+ e PKR-/- machos foram inoculados com HSV1. Os grupos controle foram inoculados com HSV1 inativo. Alodínia mecânica e hiperalgesia térmica foram monitoradas antes da inoculação do vírus e 8, 14, 21 e 28 dias após a inoculação. A curva dose e temporesposta e o teste da capsaicina foram realizados no 8º e 21º dias após a inoculação do vírus. Também nos períodos herpético e pós-herpético, foi investigado o perfil de expressão de proteínas envolvidas nas vias de sinalização de PKR (PKR, eIF2?, PACT, IKK e PP2A?), assim como o efeito da inibição de PKR pelo monitoramento da fosforilação de PKR, IKK?/?, P38, JNK, ERK1,2 e STAT3, e expressão de CaMKII? e TRPV1 nos GRD (L3-L6) ipsilateralmente à pata inoculada. Alodínia mecânica e hiperalgesia térmica ficaram evidentes até 28 dias após a inoculação. Camundongos PKR-/- desenvolveram alodínia mecânica, mas não hiperalgesia térmica, quando comparados com animais PKR+/+. A inibição sistêmica de PKR reverteu a hiperalgesia térmica de modo tempo- e dose-dependente e preveniu o comportamento nocifensivo induzido por capsaicina, enquanto PKR-/- apresentaram resposta nocifensiva praticamente ausente em ambas as fases herpética e pósherpética. Houve aumento da expressão de PP2A? e da fosforilação de PKR, IKK?/? e eIF2?, durante os períodos herpético e pós-herpético, e de PACT na fase pósherpética. A inibição de PKR promoveu o aumento da fosforilação de P38 em ambas as fases, e redução da fosforilação de PLC?1 acompanhada do retorno da fosforilação de Akt e STAT3 ao nível do grupo controle e o aumento da expressão de Ca-MKII? na fase herpética. Já na fase pós-herpética, reduziu a fosforilação de JNK e Akt e a expressão de Ca-MKII?, retornou a fosforilação de ERK1,2, PLC?1 e STAT3 ao nível do grupo controle e aumentou a expressão de TRPV1. Nossos resultados indicam que a atividade de PKR desempenha papel essencial na hiperalgesia térmica induzida por infecção pelo HSV1Double stranded RNA-activated protein kinase (PKR) is a sentinel molecule activated by cellular stress conditions, including viral infections. PKR activation by phosphorylation triggers cascades involved in inflammatory response and protein synthesis suppression. Our previous data suggest that PKR is involved in the inflammatory thermal hyperalgesia. Here we investigated the role played by PKR on thermal hyperalgesia induced by herpes simplex virus type-1 (HSV-1), during herpetic and post-herpetic phases, by combining behavioral, genetic, pharmacological, and molecular methods. Adult male C57bl/6, PKR+/+ and PKR-/- mice were inoculated with HSV-1. Control groups were inoculated with inactive (mock) HSV1. Mechanical allodynia and thermal hyperalgesia were monitored before virus inoculation and 8, 14, 21, and 28 days post-inoculation. The dose- and timeresponse curve and the capsaicin test were performed at 8th and 21st days post virus inoculation. Also in the herpetic and post-herpetic periods, was investigated the expression profile of proteins involved in the PKR signaling pathways (PKR, eIF2?, PACT, IKK and PP2A?), and the effect of PKR inhibition by monitoring PKR, IKK?/?, P38, JNK, ERK1,2, and STAT3 phosphorylation, and Ca-MKII? and TRPV1 expression in the dorsal root ganglia (L3-L6) ipsilaterally to the inoculated paw. Mechanical allodynia and thermal hyperalgesia became evident until 28 days postinnoculation. PKR-/- mice developed mechanical allodynia but not thermal hyperalgesia, when compared with PKR+/+ mice. Systemic PKR inhibition reversed thermal hyperalgesia in a dose and time-dependent manner, and prevented the capsaicin-induced nocifensive behavior, whereas PKR-/- showed no nocifensive behavior almost absent in both herpetic and post-herpetic phases. There was increased expression of PP2A? and the phosphorylation of PKR, IKK?/?, and eIF2?, during herpetic and post-herpetic periods, and PACT in the post-herpetic phase. PKR inhibition increased P38 phosphorylation in both phases, and reduction of PLC?1 phosphorylation together with the return of the Akt and STAT3 phosphorylation to the control group level, and enhanced Ca-MKII? expression in the herpetic phase. At the post-herpetic phase, suppressed JNK and Akt, and Ca-MKII? expression returned ERK1,2, PLC?1 and STAT3 phosphorylation to control group level and increased TRPV1 expression. The data indicate that PKR activity plays an essential role in the HSV-1 infection-induced thermal hyperalgesia
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Scisci, Nathália. "Prevalência e características da dor neuropática e neuropatia periférica em doentes submetidos à oxaliplatina para tratamento do câncer colorretal." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-24102016-152636/.
Full textAbstract:
Dor neuropática e neuropatia causadas pelo quimioterápico oxaliplatina são comuns e causam restrições às atividades funcionais e qualidade de vida. Muitos estudos têm quantificado e qualificado esses sintomas, porém raramente utilizando amostra expressiva e instrumentos validados e específicos para este fim. Neste estudo é proposta uma análise ampla, por instrumentos que quantificam e qualificam a dor e neuropatia relacionadas à oxaliplatina e suas características associadas. Objetivos: Identificar a prevalência de dor neuropática e neuropatia periférica em doentes com câncer colorretal recebendo tratamento com oxaliplatina durante os seis meses de tratamento quimioterápico e após seguimento (de 3 a 6 meses); avaliar, comparar e descrever as características da dor e neuropatia nesta população e avaliar seu impacto nas atividades de vida diária e qualidade de vida. Métodos: Foram incluídos 110 doentes (média 55,6 anos) com câncer colorretal durante o tratamento quimioterápico com oxaliplatina e seguidos por 3 a 6 meses após quimioterapia. Os doentes responderam ao questionário sócio-demográfico e a questionários específicos para dor e neuropatia antes da quimioterapia e bimestralmente por até seis meses durante a quimioterapia e em avaliação de seguimento realizada de 3 a 6 meses após o término da quimioterapia. Os instrumentos utilizados foram: Questionário de Qualidade de Vida da Organização Européia para Pesquisa e Tratamento do Câncer - C30 (EORTC QLQ-C30); Questionário de Dor McGill reduzido (QDMR), Inventário de Sintomas de Dor Neuropática (ISDN), Inventário Breve de Dor (BPI-Brief Pain Inventory) Questionário de Dor Neuropática 4 (DN4), Escala Hospitalar de Ansiedade e Depressão (HADS), Escore Total de Neuropatia (TNS - Total Neuropathy Score). Resultados: Em geral, a dor e neuropatia aumentaram durante o período de quimioterapia e diminuíram após fim do tratamento, permanecendo em níveis significativamente mais elevados após o fim do tratamento quimioterápico. A média de intensidade de dor (dor mais intensa) segundo o IBD foi 2,54 na V3 (após 4 meses de tratamento com oxaliplatina). A dor foi do tipo neuropática em 21,67% dos doentes ao fim da quimioterapia e em 10,00% após fim do seguimento. As médias segundo o ISDN foram 0,67 no basal, 18,67 na V2, 17,77 na V3, 17,44 após quimioterapia e 11,03 após seguimento. A característica da dor mais frequente foi em choque elétrico, enjoada e incômoda segundo o QDMR e segundo o ISDN foram choque elétrico, frio doloroso e dormência. A qualidade de vida sofreu impacto negativo. Conclusões: Dor neuropática foi prevalente após a quimioterapia e após seguimento e se associou com interferência negativa sobre as atividades diárias. Estes dados poderão auxiliar o desenvolvimento de tratamentos individualizados da neuropatia relacionada à oxaliplatinaNeuropathic pain and neuropathy caused by oxaliplatin chemotherapy are common and cause restrictions in activities of daily living and quality of life. Many studies have quantified and qualified these symptoms but only rarely used a comprehensive sample of patients and employed validated and specific instruments for pain assessment. In this study we proposed a comprehensive analysis by instruments that quantify and qualify the pain and neuropathy and its characteristics. Aim of Investigation: To identify the prevalence of neuropathic pain and peripheral neuropathy in patients with colorectal cancer receiving treatment with oxaliplatin during the six months of chemotherapeutic treatment and after follow-up (3 to 6 months); to evaluate, compare and describe pain and peripheral neuropathy characteristics in this population and evaluate their impact on activities of daily living. Methods:110 patients (mean 55.6 years) with colorectal cancer were included during the six months of chemotherapy with oxaliplatin and follow-up (3 to 6 months) after chemotherapeutic treatment. Patients answered socio-demographic questionnaires and specific assessment tools for pain and neuropathy evaluation at the baseline visit and every 2 months during chemotherapy and after follow-up (3-6 months). The instruments used were: The European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30); Reduced McGill Pain Questionnaire (MPQ), Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory (BPI) Neuropathic Pain Diagnostic Questionnaire (DN4), Hospital Anxiety and Depression Scale (HADS), Total Neuropathy Score (TNS), Results: In general, pain and neuropathy intensity increased during chemotherapy and decreased after the end of treatment (follow-up). The most severe pain according to the BPI was 2.54 in V3 (after 4 months treatment with oxaliplatin). Pain was neuropathic in 21.67% right after chemotherapy and in 10.00% after follow-up according to the DN4. The average sum of neuropathic pain symptoms according to the NPSI were 0.67 in V1, 18.67 in V2, 17.77 in V3, 17.44 after chemotherapy and 11.03 after follow-up. The most common characteristics of the pain was electric shocks, nauseating and fearful, according to MPQ and according to NPSI were electric shock, evoked by cold stimuli and tingling. Conclusions: Patients treated with oxaliplatin had significant pain and neuropathy that negatively interfeared with daily activities. These data may help tailor individualized treatment of chemotherapy related neuropathic pain
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Tonezzer, Tania. "Uso da Estimulação Elétrica Nervosa Transcutânea (TENS) na redução dos sintomas de neuropatia periférica induzida por quimioterapia anti-neoplásica." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5170/tde-08032017-163417/.
Full textAbstract:
INTRODUÇÃO: A neuropatia periférica induzida por quimioterapia (NPIQ) está entre os efeitos colaterais mais comuns decorrentes da quimioterapia antineoplásica e uma das principais causas da redução da dose ou interrupção do tratamento. Os sintomas mais prevalentes são a dor e a parestesia, acarretando desconfortos crônicos e perda de habilidades funcionais, interferindo negativamente na qualidade de vida dos pacientes. Estudos recentes têm avaliado o uso da Estimulação Elétrica Nervosa Transcutânea (TENS) nesta patologia, apresentando evidências positivas na redução da dor, porém seu efeito nos sintomas de parestesia e nas atividades de vida diária destes pacientes ainda não foram avaliados. OBJETIVO: Investigar os efeitos da Estimulação Elétrica Nervosa Transcutânea (TENS) nos sintomas de dor, parestesia e nas atividades de vida diária da NPIQ em indivíduos com diagnóstico de câncer de mama e colorretal, submetidos ao tratamento de quimioterapia. MÉTODOS: Trata-se de um ensaio clínico duplo-cego, controlado, randomizado e multicêntrico, com abordagem quantitativa, em pacientes submetidos ao tratamento de quimioterapia, contendo em seu protocolo os seguintes quimioterápicos: paclitaxel e oxaliplatina. Os sujeitos da pesquisa utilizaram o dispositivo terapêutico TENS com modulação de frequência entre 7 e 75 Hz na região distal dos membros, no local de maior desconforto, com intervenções diárias de 60 minutos, durante três ciclos de quimioterapia (45 dias). Os participantes foram divididos em dois grupos: grupo TENS ativa (GTA) e grupo TENS placebo (GTP). A avaliação dos efeitos da TENS foi medida através dos seguintes instrumentos: a Escala Visual Analógica (EVA) para avaliar os sintomas de dor e parestesia e Questionário de Neurotoxicidade Induzida por Anti-neoplásicos (QNIA) para avaliação dos sintomas da NPIQ. RESULTADOS: Finalizaram a pesquisa 24 pacientes. Não se observou uma diferença significativa entre os 2 grupos no que se refere ao desfecho primário de redução dos sintomas de dor (p = 0.666), parestesia (p = 0,673) e impacto da TENS na frequência dos sintomas (p = 0,5906) e atividades de vida diária (p = 0,8565). CONCLUSÃO: Estes resultados sugerem que a TENS aplicada no modo de modulação de frequência não foi eficaz para melhorar os sintomas de neuropatia periférica induzida por quimioterapia, durante os ciclos de quimioterapia. Não houve, porém, agravamento dos sintomas em ciclos subsequentes ao início dos sintomas da doençaBACKGROUND: Peripheral neuropathy induced by chemotherapy (PNIC) is amongst the most common side effects derived from antineoplastic chemotherapy and one of the principal causes of dose reduction or treatment interruption. The most prevalent symptoms are pain and numbness, resulting from chronic discomfort to loss of functional abilities, negatively affecting quality of life and autonomy of patients. Recent studies have evaluated the use of Transcutaneous Electrical Nerve Stimulation (TENS) in this disease, pointing to evidence of pain reduction, but its effect on symptoms of paresthesia and in daily life activities have not yet been evaluated. OBJECTIVE: To investigate the effects of Transcutaneous Electrical Nerve Stimulation (TENS) for reducing the symptoms of pain, paresthesia and the daily activities of PNIC in patients diagnosed with breast cancer and colorectal cancer undergoing chemotherapy treatment. METHODS: It is a double-blind, controlled, randomized, multicenter clinical trial with a quantitative approach in a sample of 24 patients undergoing chemotherapy treatment, containing in its protocol the following chemotherapeutic agents: paclitaxel and oxaliplatin. The research subjects used the TENS therapeutic device with frequency modulation between 7 and 75 Hz in the distal limb, on the location of greatest discomfort with daily interventions lasting 60 minutes for three chemotherapy cycles (45 days). Participants were divided into two groups: active TENS group (ATG) and placebo TENS group (PTG). The assessment of the effects of TENS was measured by the following instruments: The Visual Analogue Scale (VAS) to assess the symptoms of pain and numbness and Questionnaire for Neurotoxicity Induced by Anti-neoplastic (QNIA) to assess the symptoms of PNIC. RESULTS: A 24-patient study was completed. There was no significant difference between the two groups regarding the primary endpoint of reduced pain symptoms (p = 0.666) and paresthesia (p = 0.673), neither any measurable impact of TENS in the frequency of symptoms (p = 0.5906) or activities of daily living (p = 0.8565). CONCLUSION: These results suggest that TENS applied in frequency modulation mode is not effective for ameliorating the symptoms of peripheral neuropathy induced by chemotherapy during chemotherapy cycles. There was, however, no worsening of symptoms in subsequent cycles after the onset of symptoms
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Oladapo, Abiola Oluwagbenga. "Examining adherence with medications used in treating diabetic peripheral neuropathic pain." Thesis, 2010. http://hdl.handle.net/2152/ETD-UT-2010-08-1673.
Full textAbstract:
The present study is a retrospective cohort analysis which sought to examine adherence to medications used in managing painful diabetic peripheral neuropathy (PDPN) and to determine their association with oral antidiabetic (OAD) medication adherence using the Texas Medicaid prescription claims database. The study objectives were to: 1) provide a description of PDPN and OAD medication use among the study subjects; 2) determine if PDPN medication adherence differs among individual PDPN agents (i.e., tricyclic antidepressants, gabapentin, pregabalin and duloxetine); 3) determine if pre-index OAD and post-index OAD medication adherence differs among mono, dual, and triple OAD therapies; and 4) determine if PDPN medication adherence is related to post-index OAD medication adherence while controlling for covariates. Study participants were adult (≥18 years) Medicaid beneficiaries prescribed OAD and PDPN medications. The index date was the first PDPN prescription. Data were extracted from June 1, 2003 to October 31, 2009 and prescription claims were analyzed over an 18-month study period (i.e., 6 months pre-index and 12 months post index period). Medication possession ratio (MPR) was used as a proxy measure of medication adherence. An MPR less than 80 percent was regarded as being non-adherent to prescribed medication, while an MPR greater than or equal to 80 percent was regarded as being adherent to prescribed medication. Objective 1 was addressed using descriptive statistics (i.e., mean, standard deviation, frequency). Univariate analysis (ANOVA) was employed to address Objectives 2 and 3. Multivariate analyses (i.e., multiple linear regression and logistic regression) were conducted to address Objective 4. For the logistic regression MPR was dichotomized at the cut-off value of 80 percent.
A total of 4,277 patients met the study’s inclusion criteria. The overall mean MPR (±SD) for PDPN medications was 75.4 percent (±23.9). Mean MPR (±SD) was highest for duloxetine (85.6% ±18.2) and was lowest for pregabalin (69.4% ±24.9). Mean MPR differed significantly among individual PDPN medications (p<0.0001). The overall mean MPR (±SD) for OAD medications in the pre and post-index period was 73.0 percent (±24.3) and 64.5 percent (±25.6) respectively. In both pre and post-index periods, mean MPR differed significantly among mono, dual, and triple OAD therapies (p<0.0001). In the pre-index period, mean MPR (±SD) was highest for monotherapy users (75.4% ±24.7) and was lowest for triple therapy users (63.9% ±22.9). Similarly, mean MPR (±SD) was highest for monotherapy users (69.0% ±26.1) and was lowest for triple therapy users (52.9% ±21.8) in the post-index period. After controlling for the covariates, PDPN adherence (i.e., MPR) was statistically significant (p<0.0001) and positively related to post-index OAD adherence (i.e., MPR). PDPN patients who were non-adherent (i.e., MPR<80%) to their PDPN medications (or neuropathic pain medications), compared to those who were adherent (MPR≥80%), were significantly less likely to be adherent to their OAD medications [Odds Ratio (OR) = 0.626, 95% CI=0.545-0.719]. In addition, post-index OAD adherence (i.e., MPR) did not differ significantly (p>0.05) when pregabalin, duloxetine and gabapentin users were individually compared to tricyclic antidepressants users.
In conclusion, PDPN patients who were adherent (i.e., MPR≥80%) to their PDPN medications, compared to those who were not adherent (i.e., MPR<80%), were more adherent to their OAD medications. Also, adherence to OAD medications was independent of the type of PDPN medication used. PDPN patients need to be educated regularly that neuropathic pain medications only relieve the pain associated with the neuropathy but achieving adequate glycemic control remains the only established approach for slowing down the progression of the neuropathy and other complications associated with the diabetes.text
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Lee, Wen, and 李雯. "The role of CXCL7 in peripheral nerve injury-induced neuropathic pain." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/4z4g6p.
Full textAbstract:
碩士國立臺灣大學
藥理學研究所
105
Neuropathic pain is a problem in general population because of the complexity of neuropathic symptoms, poor outcomes and difficult treatment decision. Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system and can be subtyped as central and peripheral neuropathic pain. Until now, conventional pharmacological treatments for neuropathic pain are effective in <50% of patients. Therefore, clarifying actual mechanism in neuropathic pain and finding a new target remain important parts for developing new drugs. Neuroinflammation has been reported to be involved in the pathophysiology of neuropathic pain and is an emerging target of treatment. Although the cytokine/chemokine pathways play a major role in neuroinflammation, the exact mechanism in neuropathic pain remains unclear. To investigate the cytokines/chemokines changes, we used neuropathic pain animal model produced by unilateral L5 spinal nerve ligation-and-cut (SNL) and electronic von Frey test and plantar test for pain assessment (including mechanical and thermal hyperalgesia, respectively). We then screened cytokine expression in the cerebrospinal fluid using cytokine array, and it was found that CXCL7 increased markedly in SNL rats compared with control. The expression levels of both protein and messenger RNA of CXCL7 were up-regulated in spinal cord dorsal horn samples of SNL rats compared with control.Furthermore, intrathecal administration of recombinant chemokine CXCL7 induced mechanical and thermal hyperalgesia and increased glia activation and sensory neuropeptide CGRP expression level. To investigate the involvement of CXCR1/CXCR2, receptors of CXCL7, a CXCR1/CXCR2 antagonist reparixin-L-lysine salt (reparixin) was co-administered intrathecally with CXCL7 via osmotic pump. It was found that CXCR1/CXCR2 antagonist reversed CXCL7-induced hyperalgesia. We also evaluated the effect of CXCR1/CXCR2 in SNL rats. Right after SNL, intrathecal infusion of CXCR1/CXCR2 antagonist reparixin via osmotic pump for 7 days attenuated SNL-induced hyperalgesia and glia activation. These results indicate that CXCL7 might be involved in neuropathic pain and CXCR1/CXCR2 antagonist might be developed as drug for the treatment of neuropathic pain.
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Hong, Shao-Fu, and 洪韶甫. "Laser acupuncture attenuates neuropathic pain and paresthesia for gastrointestinal cancer patients with oxaliplatin-induced peripheral neuropathy." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/70344431657549304873.
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Chang, Yu-Cheng, and 張宇晟. "Increased expression of Kv4.3 channel complex in nociceptors reduces peripheral neuropathic pain." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/80811175800238951774.
Full textAbstract:
碩士國立陽明大學
神經科學研究所
103
Kv4 channels, a subfamily of voltage-gated K+ (Kv) channels that evoke A-type potassium currents, play a crucial role in controlling neuronal excitability. Accumulative evidence suggest that native Kv4 channels function in ternary complex comprising Kv4 α-subunits and accessory β-subunits, including cytosolic Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-like proteins (DPPLs). Compared with Kv4 α-subunits alone, A-type potassium currents are robustly increased when they are coexpressed with β-subunits in heterologous systems. Neuropathic pain is often induced by peripheral nerve injury. Our previous studies have demonstrated that Kv4.3 is expressed in the somata of a subset of non-peptidergic nociceptors within the dorsal root ganglion (DRG), Kv4.3 protein level is greatly reduced after peripheral nerve injury, and knockdown of Kv4.3 expression in nociceptors can induce pain in naïve rats. Here, to investigate whether increasing Kv4.3 protein level can relieve neuropathic pain, we used unilateral L5/L6 spinal nerve ligation (SNL) in rats as an animal model. Kv4.3 cDNA was transfected into rat lumbar DRG neurons by a nonviural vector polyethylenimine (PEI) through intrathecal injection. Intrathecal injection of Kv4.3 cDNA slightly attenuated SNL-induced mechanical hypersensitivity (a major symptom of neuropathic pain) by increasing Kv4.3 protein expression in the ipsilateral L5/L6 DRGs. In addition, co-injection of Kv4.3 and its auxiliary subunit cDNAs greatly attenuated SNL-induced mechanical hypersensitivity. Furthermore, SNL-induced nociceptor activity is reduced more by Kv4.3/KChIP1/DPP10 cDNAs than by Kv4.3 cDNA alone. These data suggest that Kv4.3 and its auxiliary subunits KChIP1/DPP10 are potential targets for treating peripheral neuropathic pain.
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Pinto, Joana Manuela Tenreiro. "A retrospective analysis of the efficacy of treatment of neuropathic peripheral pain." Master's thesis, 2016. http://hdl.handle.net/10316/41864.
Full textAbstract:
Tese de mestrado, apresentado á Faculdade de Medicina da Universidade de CoimbraIntroduction: Neuropathic pain is defined as pain arising from a direct consequence of lesion or disease affecting the somatosensory system. Although there are several guidelines for neuropathic pain managent and various effective drugs are accessible, neuropathic pain remains untreated or undertreated. The goal of this study was to evaluate retrospectively efficacy of combining topic capsaicin 8% with oral neuropathic pain therapy in peripheral neuropathic pain/localized neuropathic pain, by measuring pain intensity and pain treatment area reduction. Methods: This retrospective study was conducted at the Chronic Pain Unit in the Hospitalar Center Tondela-Viseu, Portugal. Forty-three patients with either post-herpetic neuralgia or post-traumatic/post-surgical neuropathic pain with localized allodynia and submitted to a combined therapy with oral neuropathic pain medication (opioids, anticonvulsants, antidepressants) and topical capsaicin 8% were enrolled. Therapeutic efficacy was evaluated considering pain intensity and treatment area variables. Pain intensity was assessed at baseline and 7-14 days after each treatment, using the numerical pain rating scale (NPRS). Treatment pain area was assessed at baseline and after each treatment. Results: The median percentage reduction in NPRS score was -40.0, [-50.0,-33.3] (95% CI, bootstrap) and the median percentage reduction in treatment pain area was -35.1 [- 50.9, 3.4] (95% CI, bootstrap). There was no significant difference in efficacy between postherpetic and post-traumatic/postsurgical neuropathic pain. No differences were detected in pain intensity and pain treatment area reduction regardless the use of different concomitant oral pain medication. Conclusion: This study evaluates clinical efficacy of combined topical capsaicin and oral neuropathic pain therapy in PNP/localized neuropathic pain by combining NPRS scores and treatment area assessment. This study newly demonstrates that combined medication significantly reduces both peripheral neuropathic pain and treatment pain area in localized neuropathic pain.
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Guzman, Ruben J. (Ruben Jacobo). "Effect of whole-body vibration on painful diabetic peripheral neuropathy." Thesis, 2012. http://hdl.handle.net/1957/30035.
Full textAbstract:
Introduction. Painful diabetic peripheral neuropathy (DPN) is a common
complication of diabetes that interferes with daily living and causes severe
pain. Pharmacotherapy is the accepted treatment strategy, however, this
strategy is associated with high cost, minimal reductions in pain, and adverse
side effects. Thus, a critical need exists to develop alternative treatment
strategies. Purpose. To determine if a 12-week whole-body vibration (WBV)
intervention reduces pain in adults with DPN. Methods. Twenty-one adults
with physician confirmed painful DPN volunteered to take part in a 26-week
time series design study. Pain was assessed with the Brief Pain Inventory
Short Form [BPI-sf] and a 0-10 numeric rating scale [NRS]. The BPI-sf
contains two indices that respectively measure how pain interferes with daily
living and severity. The intervention began after a 12-week control period. At
week 13, participants were asked to stand on a WBV machine 3 d/week for 4,
3-min bouts at 30-50 Hz with 1-min rest intervals between bouts. Pain levels
were reported using the NRS before and after each bout. Results. Comparing
post- to pre-intervention, BPI-sf pain interference scores decreased from
5.61±1.40 to 2.39±1.82 (p≤0.001). BPI-sf pain severity scores decreased
from 5.1±0.64 to 3.1±1.87 (p≤0.01). Analyses of the NRS scores indicate
that pain decreased each week following WBV and that between weeks, pain
continued to decrease. Conclusion. These findings demonstrate that whole-body
vibration was effective at reducing pain in a sample of adults with painful
DPN.Graduation date: 2012
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Holdridge, SARAH. "INVESTIGATING THE EFFECTS OF PERIPHERAL NERVE INJURY ON δ OPIOID RECEPTOR EXPRESSION AND FUNCTION: IMPLICATIONS FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN." Thesis, 2009. http://hdl.handle.net/1974/1762.
Full textAbstract:
Neuropathic (NP) pain is a debilitating chronic pain disorder that is a challenge to diagnose and an even greater challenge to treat. Commonly described as burning or shock-like, NP pain is characteristically resistant to traditional analgesic therapy. This thesis project aimed to investigate the potential therapeutic benefit of delta opioid receptor (δOR)-selective agonists in the management of NP pain. In the current experiments, rats that underwent unilateral sciatic nerve injury displayed characteristic behavioural manifestations including cold and thermal hyperalgesia as well as tactile allodynia in the ipsilateral hind paw. The spinal administration of DLT, a δOR-selective agonist, dose-dependently reversed tactile allodynia in NP rats and attenuated cold and thermal hypersensitivities. Moreover, DLT produced greater antinociceptive effects in NP rats compared with controls in the cold water paw withdrawal, hot water tail flick, and thermal plantar box tests. Nerve injury-induced augmentation in δOR function was dependent on nociceptive afferents, since the effect was absent in NP rats that received neonatal treatment with capsaicin. Furthermore, it was not due to increased δOR biosynthesis as western blots and immunohistochemistry revealed no change in spinal δOR protein. We hypothesized that an alternative mechanism, such as redistribution of receptors within the neuron, may underlie δOR function changes. Using immunogold electron microscopy, we showed that nerve injury indeed increased the cell surface expression of δORs within dendritic profiles of the dorsal horn via redistribution of existing receptors. Interestingly, this event was observed bilaterally in the deep dorsal horn, with no effect in the superficial laminae. The mechanisms underlying nerve injury-induced δOR trafficking remain unclear however we may take cues from other δOR trafficking events. We showed that concomitant treatment of rats with morphine and a glial inhibitor prevented both the activation of spinal glia and the changes in δOR agonist effects observed with morphine alone, suggesting that glial activity contributes to morphine-induced δOR trafficking in vivo and may provide insight into the mechanisms underlying nerve injury-induced δOR trafficking. Collectively, these studies reveal an important role of δORs in modulating pain symptoms associated with nerve injury, supporting further exploration of δORs as novel therapeutic targets in the treatment of NP pain.Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2009-04-20 14:46:29.83
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Leitch, Jordan Kelly. "Functional Magnetic Resonance Imaging of Peripheral Neuropathic Pain in the Spinal Cord and Brainstem." Thesis, 2010. http://hdl.handle.net/1974/5960.
Full textAbstract:
To date, most studies investigating the neural signature of pain in humans have focused on the brain, and those studies concerned with more caudal areas (such as the spinal cord (SC) or brainstem) have used only experimental models of pain. The objectives of this study were 1) to determine the neural activity in the human brainstem and SC that is caused by a noxious mechanical stimulus and 2) to compare the neural response to noxious stimuli in healthy controls and a patient population diagnosed with peripheral neuropathic pain. The SC and brainstem contain important synaptic points in several major pain pathways, and comparing the neural response between a control and patient population in these areas provides a more complete picture of healthy and pathological pain processing.
Functional MRI studies of the SC and brainstem were carried out in healthy control subjects and patients diagnosed with carpal tunnel syndrome (CTS) in a 3T Siemens Magnetom Trio. Subjects reported the point at which the pressure (in mmHg, applied to the wrist at the location of the median nerve) corresponded to a pain level of 2, 4, and 6 on a numerical 11 point pain scale. Spatially normalized group results superimposed on anatomical templates in the axial orientation were visually identified using several stereotaxic atlases.
We observed consistent signal intensity change in areas implicated in the transmission and modulation of pain in both control and CTS groups. Both groups showed a similar decrease in signal change with increasing pain, as results at pain level 2 are predominantly positive signal change and at pain level 6 are typically negative. This may indicate a reduction in the tonic inhibition of painful sensations. Differences between groups were readily visible in regions anatomically consistent with the dorsal horn (DH) of the cervical SC, rostral ventromedial medulla (RVM), dorsolateral pontine tegmentum (DLPT), and midbrain periaqudectal gray (PAG). The anatomical variation in signal change between groups may represent, for the first time, a visualization of the functional difference between healthy and pathological pain processing in the SC and brainstem using spinal fMRI.Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-08-03 14:46:01.7
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Constantin, Cristina [Verfasser]. "Peripheral mechanisms of neuropathic pain following nerve lesion : neurophysiological and behavioural experiments / vorgelegt von Cristina Constantin." 2004. http://d-nb.info/971934703/34.
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Li, Yung-Tsung, and 李泳璁. "Two exercise training reduce peripheral neuropathic pain and protect nerve damage following chronic constriction injury of sciatic nerve in rats." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/86877728785527761228.
Full textAbstract:
碩士中國醫藥大學
物理治療學系復健科學碩士班
98
Background: Pharmacotherapies provide an effective efficacy for treatment of neuropathic pain, but they produce side effects. The mechanism of exercise on neuropathic pain is not clear. The aim of this study was to investigate whether exercise training, a non-pharmacotherapy method, provide beneficial effects on neuropathic pain. Materials and Methods: Male Sprague Dawley rats that suffered for chronic constriction injury (CCI) with/without exercise were used. All rats were divided into 7 groups: control, sham operated, sham operated with swimming or treadmill exercise, CCI, CCI with swimming or treadmill exercise. We observed body weight, thermal hyperalgesia and mechanical allodynia in all groups. The expression of heat shock protein 72 (HSP72) and pro-inflammatory cytokines (tumor necrosis factor-α and interlukin-1β) in sciatic nerve were detected by immunoblotting or ELISA, respectively. We also investigated the morphological change of sciatic nerve after CCI treatment. Results: The body weight in sham operated with swimming or treadmill exercise, CCI, CCI with swimming or treadmill exercise groups was heavier than that in control and sham operated groups. In control, sham operated, sham operated with swimming or treadmill exercise groups, rats showed no thermal hyperalgesia and mechanical allodynia until day 39 after CCI-treatment. CCI rat with swimming (hyperalgesia, P<0.05; allodynia, P<0.01) or treadmill exercise (hyperalgesia, P<0.05; allodynia, P<0.01) attenuated thermal hyperalgesia and mechanical allodynia significantly, when compared with CCI rats with exercise 21 days after CCI-treatment. We also found that swimming and treadmill exercise reduced tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) expression in sciatic nerve 22 or 40 days after CCI-treatment. HSP72 expression in sciatic nerve increased in CCI with treadmill exercise group (P< 0.05), but not in CCI with swimming exercise group, compared with CCI group 22 or 40 days after CCI-treatment. The morphological improvements seen in sciatic nerve in CCI with treadmill or swimming exercise group, compared with CCI group on 22 or 40 days after CCI-treatment. Conclusions: This study indicated that swimming and treadmill exercise partially ameliorates thermal hyperalgesia, mechanical allodynia, TNF-α and IL-1β expression in sciatic nerve. Treadmill exercise, but not swimming exercise, increased HSP72 expression in sciatic nerve of CCI with exercise rats, compared with CCI without exercise rats. Both of treatment with swimming and treadmill exercise promotes restoration of morphological and functional properties following CCI.
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Lu, Ling-Chun, and 盧怜君. "The Relationships of Chemotherapy Induced Peripheral Neuropathic Pain, Activities of Daily Lives, Mood, and Quality of Life in Patient with Colorectal Cancers." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/43271838190560887976.
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碩士國立臺北護理健康大學
護理研究所
100
The purpose of this study was to investigate the relationships of chemotherarpy induced neuropathic pain, activies of daily lives, mood and quality of life among patients with colorectal cancer in Taiwan. A convenience sample was used in this cross-sectional study. The data was collected by self-administrated questionnaires. The instruments included Neuropathic Pain Symptom Inventory (NPSI)、Screening of Activity Limitation and Safety Aweareness Scale (SALSA scale）、Profile of Mood States short form (POMS SF）and Functional Assessment Cancer Therapy-Colorectal instruments version 4 (FACT-C version 4) as well as self-constructed items. A total of 106 questionnaires were distributed. The results revealed majority of the participants were male (53.8%) and married (77.4%). The average age was 56.92(SD=11.35). The level of education and occupation in most participants were senior high school (29.2%) and housekeeper (20.8%). The stage of cancer in most participants was stage III (60.4%) and IV (34.0%). There was history of chronic disease in the majority of the participants (63.2%) as well as history of post radical resection following by oxaliplatin/ 5-Fu-based chemotherapy (FOLFOX) (95.3%). On the incidence of chemotherapy induced neuropathic pain, majority of the participants is slight (93.4%). The severity of chemotherapy induced neuropathic pain from high to low was paraesthesia, intermittently neuropathic pain, induced neuropathic pain, and spontaneously neuropathic pain, subsequently. On the domain of activities of daily lives, minority of the participants is slight restriction (11.3%). The restrictive severity of activities of daily lives from high to low was self-care, work of hand, dexterity of hands and mobility of feet, subsequently. The score of each domain in mood from high to low was vigor-activity, confusion-bewilder, fatigue-inevtia, tension-anxiety, depression- dejection, and anger-hostility, subsequently. The results indicated that there were a low positive correlation between paraesthesia and dexterity of hands (r＝.196, p<.05), a medium positive correlation between neuropathic pain and mood (r＝.492, p<.001), a medium negative correlation between spontaneously neuropathic pain and quality of life (r＝-.254, p<.01). In additional, a medium positive correlation between activities of daily lives and mood (r＝.388, p<.01), a medium negative correlation between activities of daily lives and quality of life (r＝-.328, p<.01) and a high negative correlation between mood and quality of life were reported (r＝-.615, p<.001). Results from the hierarchical multiple regression analysis detected that stage, accumulative dose of chemotherapy, spontaneously neuropathic pain, and activies of daily lives were determinants in quality of life before mood was included. They can explained 45.2% of the variance on quality of life. Furthermore, the mediating effects of perceived mood on quality of life was analyzed by ordinary least square multiple regression analysis. The result showed 42.51% variance of spontaneously neuropathic pain on quality of life and 43.17% variance of activies of daily lives on quality of life could explained by perceived mood. The result from the current study may provide new insight into status and relationships of chemotherapy induced neuropathic pain, activies of daily lives, mood and quality of life among the patients with colorectal cancer. Strategies which aim to improve the quality of life among patients with colorectal cancer may be developed through the enhancement of nursing evaluation of chemotherapy induced neuropathic pain, activities of daily lives and mood, as well as strengthening management of care guideline.
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Stemkowski, Patrick. "The effect of long-term interleukin-1 beta exposure on sensory neuron electrical membrane properties: implications for neuropathic pain." Phd thesis, 2011. http://hdl.handle.net/10048/1713.
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The effect of interleukin-1 beta (IL-1β) on the electrical properties of sensory neurons was assessed at comparable levels and exposure times to those found in animal models of neuropathic pain. Experiments involved whole cell current- or voltage-clamp recordings from rat dorsal root ganglion (DRG) neurons in defined medium, neuron enriched cultures.
5-6 days exposure to 100 pM IL-1β produced neuron specific effects. These included an increase in the excitability of medium diameter and small diameter isolectin B4 (IB4)-positive neurons that was comparable to that found after peripheral nerve injury. By contrast, a reduction in excitability was observed in large diameter neurons, while no effect was found in small diameter IB4-negative neurons.
Further characterization of changes in medium and small IB4-positive neurons revealed that some, but not all, effects of IL-1β were mediated through its receptor, IL-1RI. Using appropriate voltage protocols and/or ion substitutions, it was found that neuron specific changes in several ionic currents, including alterations in hyperpolarization activated inward current (IH) and decreases in various K+ currents contribute to the increased excitability produced by IL-1β.
Overall, these studies revealed that:
1. The effects of long-term exposure of DRG neurons to IL-1β are reflective of the enduring increase in primary afferent excitability reported after peripheral nerve injury. This expands the recognized role of IL-1β in acute inflammatory pain to neuropathic pain.
2. Hyperexcitability in medium neurons exposed to IL-1β likely includes mixed populations of neurons corresponding to nociceptive and non-nociceptive primary afferent fibres and, therefore, has relevance to hyperalgesia and allodynia, respectively.
3. The responsiveness of small IB4-positive neurons, but not IB4-negative, to prolonged IL-1β exposure is consistent with the suggestion that small IB4-negative afferents are involved in inflammatory pain, while small IB4-positive afferents are involved neuropathic pain.
4. The identification of receptor mediated effects and several contributing ionic mechanisms, may have relevance to the development of new therapeutic approaches to neuropathic pain.
5. IL-1β can contribute to increased neuronal excitability by mechanisms that are independent of IL-1RI signalling. This should be taken into account when targeting IL-1β, or more specifically IL-1RI, in the management of neuropathic pain.
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Taylor, Keri S. "Sensorimotor Recovery, Functional and Structural Brain Plasticity, and the Development of Chronic Pain Following Upper Limb Peripheral Nerve Transection and Microsurgical Repair." Thesis, 2010. http://hdl.handle.net/1807/26519.
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Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.
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Feldman, Polina. "The role of high mobility group box 1 and toll like receptor 4 in a rodent model of neuropathic pain." Thesis, 2013. http://hdl.handle.net/1805/3692.
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Indiana University-Purdue University Indianapolis (IUPUI)Neuropathic pain is a serious health problem that greatly impairs quality of life. The International Association for the Study of Pain (IASP) defines neuropathic pain as ‘pain arising as a direct consequence of a lesion or disease affecting the nervous system’. It is important to note that with neuropathy the chronic pain is not a symptom of injury, but rather the pain is itself a disease process. Novel interactions between the nervous system and elements of the immune system may be key facets to a chronic disease state. One of particular note is the recent finding supporting an interaction between an immune response protein high mobility group box 1 (HMGB1) and Toll like receptor 4 (TLR4). HMGB1 is an endogenous ligand for TLR4 that influences the induction of cytokines in many non-neuronal cells. After tissue damage or injury, HMGB1 may function as a neuromodulatory cytokine and influence the production of pro-nociceptive mediators altering the state of sensory neurons. Very little is known about the HMGB1-TLR4 interaction in sensory neurons and whether chronic changes in endogenous HMGB1 signaling influence the establishment of neuropathic pain. This thesis aims to determine whether a physiologically relevant neuroimmune interaction involving endogenous HMGB1 and TLR4 in the dorsal root ganglia is altered following a tibial nerve injury model of neuropathic pain. I hypothesized that sensitization of sensory neurons following a peripheral nerve injury is dependent on endogenous HMGB1 and TLR4. The studies presented here demonstrate that HMGB1 undergoes subcellular redistribution from the nucleus to the cytoplasm in primary afferent neurons following peripheral nerve injury. Further, the presence of extracellular HMGB1 may directly contribute to peripheral sensitization and injury-induced tactile hyperalgesia. Though thought to be important as a pivotal receptor for HMGB1 activation, neuronal protein expression of TLR4 does not appear to influence the effects of HMGB1-dependent behavioral changes following peripheral nerve injury. Taken together, these findings suggest that extracellular HMGB1 may serve as an important endogenous cytokine that contributes to ongoing pain hypersensitivity in a rodent model of neuropathic pain.
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Linton, Patrick. "Involvement of Lysophosphatidic Acid in Peripheral Neuropathy and Osteoarthritic Pain in Rats." 2013. http://hdl.handle.net/10222/35464.
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A recent study discovered elevated levels of lysophosphatidic acid (LPA) in the synovial fluid of OA patients (Eli Lilly, unpublished). LPA is required for the initiation of neuropathic pain (Inoue, 2004), and therefore, elevated levels are indicative of a neuropathic pain state. The present study attempted to determine: if 1) LPA causes neuronal damage to joint afferents, and 2) if LPA is responsible for a neuropathic pain component in OA. The experimental OA model monosodium iodoacetate (MIA) was found to cause demyelination to the saphenous nerve at 14 days post-treatment. Selective LPA antagonism prevented this damage, implicating LPA in this novel pain state. The present study concluded that 1) neuropathic pain is a component of OA, and 2) LPA facilitates the initiation of this neuropathic pain. These new findings will allow better understanding of disease etiology and may lead to the emergence of an entirely new line of OA therapeutics.
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Tseng, Ming-Tsung, and 曾明宗. "Peripheral and Central Mechanisms of Thermal and Pain Processing in Healthy Human and Neuropathy." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/49716754787112270142.
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博士臺灣大學
臨床醫學研究所
98
One of the most popular reasons that people come to the hospital for help is the symptoms caused by abnormal somatosensation, particularly pain. Many pain syndromes, particularly neuropathic pain, are usually refractory to medical treatment, which affect the psychophysical well-beings and become a burden on social economics. However, the incomplete understanding about the peripheral and central mechanisms of somatosensory processing impedes the development of new therapeutic strategies. By applying the punch skin biopsy technique with quantification of the intraepidermal nerve fibre (IENF) density to investigate the peripheral nervous system and functional MRI in the central nervous system (CNS), we aim to clarify the mechanisms of thermal and pain processing in healthy human and neuropathy. The purpose in the first part of our study is (1) to investigate the role of the IENF in the processing of somatosensation in the peripheral nervous system, and (2) to understand the clinical significance and mechanisms of cutaneous denervation in systemic lupus erythematosus (SLE). We assessed IENF density of the distal leg in 45 SLE patients (4 males and 41 females, aged 38.4 ± 13.6 years) and analysed its correlations with pathology, lupus activity, sensory thresholds and electrophysiological parameters. Compared with age- and gender-matched control subjects, SLE patients had lower IENF densities (3.08 ± 2.17 versus 11.27 ± 3.96 fibres/mm, P < 0.0001); IENF densities were reduced in 38 patients (82.2%). Pathologically, 11 patients (24.4%) were found to have definite cutaneous vasculitis; the severity and extent of cutaneous vasculitis were correlated with IENF densities. Patients with active lupus had even lower IENF densities than those with quiescent lupus (1.86 ± 1.37 versus 4.15 ± 2.20 fibres/mm, P = 0.0002). By linear regression analysis, IENF densities were negatively correlated with the SLE disease activity index (r = 0.527, P = 0.0002) and cumulative episodes of lupus flare-up within 2 years before the skin biopsy(r = 0.616, P = 0.0014). Clinically, skin denervation was present not only in the patients with sensory neuropathy but also in the patients with neuropsychiatric syndrome involving the CNS. SLE patients had significantly elevated warm threshold temperatures (P = 0.003) and reduced cold threshold temperatures (P = 0.048); elevated warm threshold temperatures were associated with the reduced IENF densities (P = 0.032). Taken together, we provide several lines of evidence that IENF reflects thermal and pain sensation, and skin biopsy with quantification of the IENF density was proved as a objective tool to evaluate temperature sensation in the peripheral nervous system. Cutaneous vasculitis and lupus activities underlie skin denervation with associated elevation of thermal thresholds as a major manifestation of sensory nerve injury in SLE. The aim in the second part of our study is to understand the response patterns to innocuous heat (IH) and noxious heat (NH) in the brain. Whether IH-exclusive brain regions exist and whether patterns of cerebral responses to IH and NH stimulations are similar remain elusive. We hypothesized that distinct and shared cerebral networks were evoked by each type of stimulus. Twelve normal subjects participated in a functional MRI study with rapidly ramped (up to 20 °C/sec) IH (38 °C) and NH (44 °C) applied to the right foot. Group activation maps demonstrated 3 patterns of cerebral activation: (1) IH-responsive only in the inferior parietal lobule (IPL); (2) NH-responsive only in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), posterior insular cortex (IC), and premotor area (PMA); and (3) both IH- and NH-responsive in the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), anterior IC, cerebellum, superior frontal gyrus, supplementary motor area, thalamus, anterior cingulate cortex (ACC), lentiform nucleus (LN), and midbrain. According to the temporal analysis of regions of interest, the IPL exclusively responded to IH, and the S2, posterior IC, and PMA were exclusively activated by NH throughout the entire period of stimulation. The IFG, thalamus, ACC, and LN responded differently during different phases of IH versus NH stimulation, and the NH-responsive-only S1 responded transiently during the early phase of IH stimulation. BOLD signals in bilateral IPLs were specifically correlated with the ratings of IH sensation, while responses in the contralateral S1 and S2 were correlated with pain intensity. In conclusion, these results suggest that unique brain areas process IH and NH differently in terms of activation location, response intensity, and phase of stimulation.
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Hammoud, Maya. "Rééducation sensitive chez des personnes présentant de l’hypoesthésie tactile et de la névralgie à la main suite à des neuropathies focales." Thesis, 2019. http://hdl.handle.net/1866/24523.
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Introduction: Les neuropathies focales (NF) peuvent entraîner de l’hypoesthésie tactile et de la douleur neuropathique spontanée (névralgie). La méthode de rééducation sensitive de la douleur décrite par Spicher et collaborateurs (MRSD) propose un traitement innovant des symptômes sensitifs des NF.
Objectifs : Chez des patients présentant une hypoesthésie tactile et de la névralgie à la main découlant d’une NF : 1) Décrire l’utilisation de la MRSD, 2) Vérifier son applicabilité, 3) Vérifier s’il y a une corrélation entre la durée requise de traitement et les caractéristiques cliniques initiales (hypoesthésie tactile, intensité douleur) des patients. 4) Décrire les changements dans l’hypoesthésie tactile et la douleur suite à la MRSD, et 5) Vérifier s’il y a une corrélation entre ces changements de sensibilité tactile et de la douleur.
Méthodologie: Une étude par série de cas rétrospective a été effectuée à partir des données de patients collectées au Centre de Rééducation Sensitive de Fribourg (Suisse) entre juillet 2004 et Octobre 2018.
Résultats: Sur 58 patients inclus dans l’étude, 42 ont complété la MRSD avec une durée requise moyenne de traitement de 124 ±104 jours. Cette durée de traitement était corrélée (rSpearman=.395) avec la sévérité des symptômes sensitifs (hypoesthésie tactile, douleur) avant la thérapie. On observe une diminution importante (p<.001) de l’hypoesthésie tactile et de la douleur entre le début et la fin du traitement. La diminution de l’hypoesthésie était modérément corrélée (rSpearman=.336) avec la diminution de la douleur.
Conclusion: La MRSD est applicable au traitement de l’hypoesthésie tactile avec névralgie à la main découlant d’une NF.Introduction: Focal neuropathies (FN) can lead to tactile hypoesthesia and spontaneous neuropathic pain (neuralgia). The Somatosensory Rehabilitation Method described by Spicher and collaborators (SRM) proposes an innovative approach to treating sensory symptoms in patients with FN. Objectives: In patients with tactile hypoesthesia and hand neuralgia arising from FN: 1) Describe the use of SRM, 2) Verify its applicability, 3) Determine if there is a correlation between the duration of treatment and patients’ clinical characteristics (tactile sensitivity and pain intensity) before therapy. 4) Describe changes in tactile hypoesthesia and pain measures subsequent to treatment with SRM, and 5) Determine if there is a correlation between changes in tactile sensitivity and changes in pain intensity in patients treated with SRM. Methodology: A retrospective case series study was carried out using data from patients admitted to the Somatosensory Rehabilitation Centre of Fribourg (Switzerland) from July 2004 and October 2018. Results: Of 58 patients included in the study, 42 completed SRM until the end of the therapy with an average duration of treatment of 124 ± 104 days. The duration of treatment was moderately correlated (rSpearman= 0.395) with the severity of sensory symptoms (tactile hypoesthesia and pain intensity) before therapy. There was a significant decrease (p <.001) in tactile hypoesthesia and pain intensity between the beginning and the end of treatment. The decrease in tactile hypoesthesia was moderately correlated (rSpearman=0 .336) with the decrease in pain. Conclusion: SRM can be used for treating tactile hypoesthesia and hand neuralgia arising from FN.
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Cunha, Ana Margarida Ferreira da. "Pain, emotion and cognition in left and right sided peripheral neuropathies: hemispheric-specific involvement of dopamine." Master's thesis, 2014. http://hdl.handle.net/1822/35019.
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Dissertação de mestrado em Ciências da SaúdePain is a complex sensation with a physiological protective role. However, in some poorly understood and individual-specific conditions, pain can chronify becoming highly debilitating and comorbid with emotional and cognitive impairments. Studies in animal models of chronic pain indicate that pain duration, left/right location and age are critically associated with the manifestation of emotional and cognitive behavioral outcomes. Paradoxically, these studies also suggest some degree of dissociation between pain and its comorbidities. Dopamine (DA) is in this context an interesting research target as it is a neurotransmitter associated with emotion, cognition and pain and its hemispheric asymmetries and age-related variations have been thoroughly demonstrated. This experimental work aims to elucidate the relation between pain and its comorbidities and to study the involvement of DA in these lateralized phenomena. First, the impact of left- and right-sided peripheral neuropathies on behavior was studied in painful and non-painful conditions. The spared nerve injury (SNI) model was installed in the left (SNI-L) or right (SNI-R) side and, 1 month later, behavior was analyzed in a battery of behavioral paradigms. SNI-L rats presented an anxiety-like phenotype in the dark/light and spontaneous burrowing behavior paradigms. Also, SNI-R rats presented increased impulsivity in variable delay-to-signal test. In both cases, side-specific effects were in accordance with previous observations of the group. Moreover, these behaviors manifested independently of the presence of allodynia, a hallmark of neuropathic pain. Secondly, D1 and D2 DA receptors’ mRNA was quantified by qPCR in the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum and nucleus accumbens in both hemispheres. Results revealed an increase in D1 and D2 expression in the nucleus accumbens contralateral to the SNI lesion. Furthermore, ablation of cortical and subcortical DA efferences resulted in heightened impulsivity in right-sided lesions suggesting a causal relation between the side of the lesion and the behavioral impairments. In conclusion, we demonstrated that the impact of a peripheral neuropathic lesion on emotional and cognitive behavior is to a certain extent independent of pain manifestations, suggesting that the nerve injury alone (i.e. in the absence of pain) can trigger central plastic events. Further studies should nevertheless be performed to clarify the relation between the peripheral nerve injury and the central events in the lateralized bias observed.
A dor é uma sensação complexa que possui uma função protetora. No entanto, em alguns indivíduos, por razões ainda não entendidas, esta pode tornar-se crónica sendo frequentemente acompanhada por problemas cognitivos e emocionais. Estudos em modelos animais de dor crónica indicam que a duração da dor, a localização à esquerda/direita e a idade estão intimamente associados com a manifestação de comportamentos emocionais e cognitivos. Paradoxalmente, estes estudos também sugerem um certo grau de dissociação entre a dor e as suas comorbilidades. A Dopamina (DA) é neste contexto um alvo de interesse, uma vez que é um neurotransmissor associado com emoção, cognição e dor. Além disso, assimetrias hemisféricas e variações relacionadas com a idade também já foram demonstradas. Este trabalho experimental tem como objetivo elucidar a relação entre a dor e as suas comorbilidades e estudar o envolvimento da DA neste fenómeno lateralizado. Inicialmente foi estudado o impacto de neuropatias periféricas esquerdas e direitas nos comportamentos emocionais e cognitivos em condições de dor e não dor. O modelo Spared Nerve Injury (SNI) foi realizado no lado esquerdo (SNI-L) ou direito (SNI-R) e 1 mês mais tarde, o comportamento foi analisado numa bateria de paradigmas comportamentais. Os ratos SNI-L demostraram um fenótipo ansioso nos testes dark/light e spontaneous burrowing. Além disso, os ratos SNI-R apresentaram um aumento de impulsividade. Nos dois casos, os efeitos do lado estão de acordo com as observações prévias do grupo. Mais ainda, estes efeitos manifestam-se independentemente da presença ou não de alodinia, uma característica da dor crónica. No segundo conjunto de experiências foi realizada a quantificação do mRNA dos receptores de DA D1 e D2 no córtex prefrontal medial, no córtex orbitofrontal, no estriado dorsal e no núcleo accumbens dos dois hemisférios. Os resultados revelaram uma expressão aumentada dos receptores no lado contralateral à lesão SNI no núcleo accumbens. Para além disso, a ablação dos eferentes corticais e subcorticais de DA resultou numa impulsividade acrescida nos animais com lesão direita sugerindo uma relação causal entre o lado da lesão e os défices comportamentais. Em conclusão, demonstramos que o impacto de uma lesão neuropática periférica é, até certa extensão, independente da manifestação da dor, sugerindo que a lesão do nervo por si só (i.e. na ausência de dor) pode despoletar eventos plásticos centrais. Estudos futuros deverão no entanto ser realizados para esclarecer a relação entre lesões periféricas do nervo, os eventos centrais e o viés de lateralidade observado.
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(8766597), Parul Verma. "Towards Understanding Neuropathy from Cancer Chemotherapy and Pathophysiology of Pain Sensation: An Engineering Approach." Thesis, 2020.
Find full textAbstract:
This thesis addresses chemotherapy-induced peripheral neuropathy (CIPN)- a form of pain sensation and a prevalent dose-limiting side-effect of several chemotherapy agents such as vincristine, paclitaxel, and oxaliplatin. These agents are used for treating various cancers such as leukemia, brain tumor, lung cancer. Peripheral neuropathy is a numbing, tingling, and burning sensation felt in the palms and feet, which occurs due to damage to neurons (nerve cells). Prolonged CIPN can impact the quality of life of cancer patients. Occasionally, severe CIPN can result in termination of chemotherapy treatment altogether. Currently, there are no established strategies for treating CIPN due to a lack of understanding of its mechanisms. Moreover, different patients react differently to the same treatment; a subgroup of patient population may never experience CIPN, while another may experience severe CIPN for the same dose. In addition, there are no established strategies for predicting CIPN either. This thesis addresses both prediction and mechanisms of CIPN.The following paragraphs reflect the organization of this thesis. Each paragraph introduces a research problem, the approaches taken to investigate it, and states the key results.
First, a metabolomics-based approach was used to investigate CIPN prediction. Blood samples of pediatric leukemic cancer patients who underwent treatment with a chemotherapy agent - vincristine were provided. These blood samples were analyzed at different treatment time points using mass spectrometry to obtain the metabolite profiles. Machine learning was then employed to identify specific metabolites that can predict overall susceptibility to peripheral neuropathy in those patients at specific treatment time points. Subsequently, selected metabolites were used to train machine learning models to predict neuropathy susceptibility. Finally, the models were deployed into an open-source interactive tool- VIPNp- that can be used by researchers to predict CIPN in new pediatric leukemic cancer patients.
Second, the focus was shifted to the pathophysiology of pain and the pain-sensing neuron; specifically: (i) investigating pain sensation mutations and the dynamics of the pain-sensing neuron, and (ii) exploring chemotherapy-induced peripheral neuropathy mechanisms.
While pain is a common experience, genetic mutations in individuals can alter their experience of pain, if any at all (certain mutations yield individuals insensitive to pain). Despite its ubiquity, we do not have a complete understanding of the onset and/or mechanisms of pain sensation. Pain sensation can be broadly classified into three types: (i) nociceptive, (ii) neuropathic, and (iii) inflammatory. Nociceptive pain arises due to a noxious external stimulus (e.g., upon touching a hot object). Neuropathic pain (which is felt as a side-effect of the aforementioned chemotherapy agents) is the numbing and tingling sensation due to nerve damage. Inflammatory pain occurs due to damage to internal tissues. Pain in any form can be characterized in terms of electrical signaling by the pain-sensing neuron. Signal transmission regarding pain occurs through generation of an electrical signal called the action potential- a peak in neuron membrane potential. Excessive firing of action potentials by a pain-sensing neuron indicates pain of a specific form and intensity. In order to investigate this electrical signaling, a mathematical modeling approach was employed. The neuron membrane was assumed to be an electrical circuit and the potential across the membrane was modeled in terms of the sodium and potassium ions flowing across it via voltage-gated sodium and potassium channels, respectively. Generation of a single action potential followed by a resting state corresponds to a normal state, whereas periodic firing of action potentials (an oscillatory state) corresponds to pain of some form and intensity in vitro. Therefore, an investigation into the switch from a resting state to an oscillatory state was proposed. A bifurcation theory approach (generally useful in exploring changes in qualitative behavior of a model) was used to explore possible bifurcations to explain this switch. Firstly, genetic mutations that can shift the pain sensation threshold in the pain-sensing neuron were explored. The detected bifurcation points were found to be sensitive to specific sodium channels’ model parameters, implying sodium channels’ sensitivity towards the pain sensation threshold. This was corroborated by experimental evidence in existing literature. Secondly, a theoretical analysis was performed to explore all possible bifurcations that can explain the dynamics of this pain-sensing neuron model. The mathematical modeling simulations revealed a mixture of small amplitude and large amplitude membrane potential oscillations (mixed-mode oscillations) for specific parameter values. The onset and disappearance of the oscillations were investigated. Model simulations further demonstrated that the mixed-mode oscillations solutions belonged to Farey sequences. Furthermore, regions of bistability- where stable steady state and periodic solutions coexisted- were explored. Additionally, chaotic behavior was observed for specific model parameters.
Finally, this thesis investigated the role of voltage-gated ion channels in inducing CIPN using the same mathematical model. Repetitive firing of action potentials in the absence of any external stimulus was used as an indicator of peripheral neuropathy. Bifurcation analysis revealed that specific sodium and potassium conductances can induce repetitive firing without any external stimulus. The findings were supplemented by recording the firing rate of a sensory neuron culture. Next, a chemotherapy agent - paclitaxel, was introduced in the model to investigate its potential effects on the firing behavior. It was seen that a medium dose of paclitaxel increased repetitive firing. This was supported by the firing rate recordings of the sensory neuron culture.
In summary, this thesis presents a prediction strategy for CIPN. Moreover, it presents a bifurcation theory-based framework that can be used to investigate pain sensation, in particular, genetic mutations related to pain sensation and chemotherapy-induced peripheral neuropathy. This framework can be used to find potential voltage-gated ion channels that can be targeted to control the pain sensation threshold in individuals, and can be extended to investigate various degeneracies in CIPN mechanisms to find therapeutic cures for it.
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Abaji, Rachid. "Using whole-exome sequencing data in an exome-wide association study approach to identify genetic risk factors influencing acute lymphoblastic leukemia response : a focus on asparaginase complications & vincristine-induced peripheral neuropathy." Thesis, 2018. http://hdl.handle.net/1866/24602.
Full textAbstract:
Le traitement de la leucémie lymphoblastique aiguë (LLA) de l’enfant, une affection d'origine maligne des cellules progénitrices lymphoïdes, s’est considérablement amélioré au cours des dernières décennies. En effet, le taux de succès du traitement a dépassé 90% dans des conditions favorables. Cependant, des toxicités liées au traitement peuvent être fatales et entrainer l’interruption ou la cessation du traitement. L'allergie, la pancréatite et la thrombose sont des complications fréquentes du traitement de la LLA et sont associées à l'utilisation de l'asparaginase (ASNase), tandis qu’une toxicité fréquente due à la vincristine (VCR) induit la neuropathie périphérique (VIPN). Étant donné que l’ajustement du schéma posologique afin d’augmenter l'efficacité et diminuer la toxicité est un processus sensible, ceci demeure un défi majeur dans plusieurs protocoles de traitement. La pharmacogénétique étudie comment des altérations de la composante génétique peuvent influer sur la variabilité interindividuelle observée dans la réponse au traitement. Une meilleure compréhension de la base moléculaire de cette variabilité pourrait améliorer considérablement les résultats du traitement, en permettant la personnalisation de ce dernier en fonction du profil génétique du patient. Des études récentes suggèrent l’avantage d’appliquer l’analyse de l’exome à la découverte de variants associés à des traits humains complexes ainsi qu’à des phénotypes de réactions médicamenteuses. L'objectif de notre travail était d'utiliser les données de séquençage pour réaliser des études d'association à l'échelle de l'exome, y compris des étapes de filtrage et de validation, afin d'identifier de nouveaux variants génétiques susceptibles de moduler le risque de développer des complications associées à ASNase et à VIPN. Douze SNP étaient associés à des complications due à l’ASNase dans la cohorte initiale, dont 3 étaient associés à une allergie, 3 à une pancréatite et 6 à une thrombose. Parmi ceux-ci, les variants rs3809849, rs11556218 et rs34708521 des gènes MYBBP1A, IL16 et SPEF2 respectivement ont été associés à des complications multiples et leur association à une pancréatite a été répliquée dans une cohorte de validation indépendante. En ce qui concerne la VCR, trois variantes ont été associées à la modulation du risque de VIPN: rs2781377 dans SYNE2, rs10513762 dans MRPL47 et rs3803357 dans BAHD1. Nous démontrons également le puissant effet combiné de la présence de plusieurs variants de risque pour chacune des toxicités étudiées et fournissons des modèles de prédiction du risque pour la pancréatite et le VIPN basés sur la méthode d’évaluation du risque génétique pondérée et qui ont été validés à l’interne. De plus, étant donné une association du polymorphisme du gène MYBBP1A avec de multiples issus de traitement, nous avons cherché à comprendre comment cette altération génétique se traduit par des variabilités de réponse aux traitements à l’ASNase. En utilisant la technique CRISPR-CAS9 pour induire l'inactivation de gènes dans des lignées cellulaires cancéreuses PANC1 (pancréatiques) nous avons testé la différence de viabilité entre les cellules inactivées et les cellules du type sauvage à la suite de la suppression du gène et du traitement par ASNase. Nos résultats suggèrent un rôle fonctionnel de ce gène dans la modulation de la viabilité, de la capacité de prolifération et de la morphologie des cellules knock-out, ainsi que dans leur sensibilité à l'ASNase, et plaident en outre pour que le gène influence l’issus du traitement de la LLA par ASNase. Le présent travail démontre que l’utilisation de l’approche de séquençage de l’exome entier dans le contexte d’une étude d’association à l’échelle de l’exome est une stratégie valide « sans hypothèse » pour identifier de nouveaux marqueurs génétiques modulant l’effet du traitement de la LLA de l’enfant, et souligne l’importance de l'effet synergique de la combinaison des locus à risque.Treatment of childhood acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells has improved significantly over the past decades and treatment success rates have surpassed 90% in favorable settings. However, treatment-related toxicities can be life-threatening and cause treatment interruption or cessation. Allergy, pancreatitis and thrombosis are common complications of ALL treatment associated with the use of asparaginase (ASNase), while vincristine-induced peripheral neuropathy (VIPN) is a frequent toxicity of vincristine (VCR). It is a sensitive process and a constant struggle to adjust the dosing regimen to ensure maximum efficacy and minimum toxicity. Pharmacogenetics studies show alterations in the genetic component between individuals can influence the observed variability in treatment response. A better understanding of the molecular basis of this variability in drug effect could significantly improve treatment outcome by allowing the personalization of ALL treatment based on the genetic profile of the patient. Emerging reports suggest the benefit of applying exome analysis to uncover variants associated with complex human traits as well as drug response phenotypes. Our objective in this work was to use available whole-exome sequencing data to perform exome-wide association studies followed by stepwise filtering and validation processes to identify novel variants with a potential to modulate the risk of developing ASNase complications and VIPN. Twelve SNPs were associated with ASNase complications in the discovery cohort including 3 associated with allergy, 3 with pancreatitis and 6 with thrombosis. Of those, rs3809849 in MYBBP1A, rs11556218 in IL16 and rs34708521 in SPEF2 genes were associated with multiple complications and their association with pancreatitis was replicated in an independent validation cohort. As for VCR, three variants were associated with modulating the risk of VIPN: rs2781377 in SYNE2, rs10513762 in MRPL47 and rs3803357 in BAHD1. We also demonstrate a strong combined effect of harbouring multiple risk variants for each of the studied toxicities, and provide internally-validated risk-prediction models based on the weighted genetic risk score method for pancreatitis and VIPN. Furthermore, given the association of the polymorphism in MYBBP1A gene with multiple treatment outcomes, we aimed at understanding how this genetic alteration translates into differences in ASNase treatment response through cell-based functional analysis. Using CRISPR-CAS9 technology we produced gene knockout of PANC1 (pancreatic) cancer cell-lines and tested the difference in viability between the knockouts and wild-type cells following gene deletion and ASNase treatment. Our results suggest a functional role of this gene in modulating the viability, proliferation capacity and the morphology of the knockout cells as well as their sensitivity to ASNase and further advocates the implication of the gene in influencing the outcome of ALL treatment with ASNase. The present work demonstrates that using whole-exome sequencing data in the context of exome-wide association study is a successful “hypothesis-free” strategy for identifying novel genetic markers modulating the effect of childhood ALL treatment and highlights the importance of the synergistic effect of combining risk loci.