Academic literature on the topic 'TRPm8 agonist'
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Journal articles on the topic "TRPm8 agonist"
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Yang, Xiao-Ru, Mo-Jun Lin, Lionel S. McIntosh, and James S. K. Sham. "Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 6 (June 2006): L1267—L1276. http://dx.doi.org/10.1152/ajplung.00515.2005.
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Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca2+ transients ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 μM) and the TRPV4 agonist 4α-phorbol 12,13-didecanoate (1 μM) evoked significant increases in [Ca2+]i in PASMCs and ASMCs. These Ca2+ responses were abolished in the absence of extracellular Ca2+ or the presence of 300 μM Ni2+ but were unaffected by 1 μM nifedipine, suggesting Ca2+ influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca2+ entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
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Yin, Ying, Son C. Le, Allen L. Hsu, Mario J. Borgnia, Huanghe Yang, and Seok-Yong Lee. "Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel." Science 363, no. 6430 (February 7, 2019): eaav9334. http://dx.doi.org/10.1126/science.aav9334.
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Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca2+)–permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo–electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP2, and Ca2+, as well as in complex with the menthol analog WS-12 and PIP2. Our structures reveal the binding sites for cooling agonists and PIP2in TRPM8. Notably, PIP2binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
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Hossain, Mohammad, Hiroshi Ando, Shumpei Unno, Yuji Masuda, and Junichi Kitagawa. "Activation of TRPV1 and TRPM8 Channels in the Larynx and Associated Laryngopharyngeal Regions Facilitates the Swallowing Reflex." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4113. http://dx.doi.org/10.3390/ijms19124113.
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The larynx and associated laryngopharyngeal regions are innervated by the superior laryngeal nerve (SLN) and are highly reflexogenic. Transient receptor potential (TRP) channels have recently been detected in SLN innervated regions; however, their involvement in the swallowing reflex has not been fully elucidated. Here, we explore the contribution of two TRP channels, TRPV1 and TRPM8, located in SLN-innervated regions to the swallowing reflex. Immunohistochemistry identified TRPV1 and TRPM8 on cell bodies of SLN afferents located in the nodose-petrosal-jugular ganglionic complex. The majority of TRPV1 and TRPM8 immunoreactivity was located on unmyelinated neurons. Topical application of different concentrations of TRPV1 and TRPM8 agonists modulated SLN activity. Application of the agonists evoked a significantly greater number of swallowing reflexes compared with the number evoked by distilled water. The interval between the reflexes evoked by the agonists was shorter than that produced by distilled water. Prior topical application of respective TRPV1 or TRPM8 antagonists significantly reduced the number of agonist-evoked reflexes. The findings suggest that the activation of TRPV1 and TRPM8 channels present in the swallowing-related regions can facilitate the evoking of swallowing reflex. Targeting the TRP channels could be a potential therapeutic strategy for the management of dysphagia.
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Amato, Antonella, Simona Terzo, Laura Lentini, Pierenrico Marchesa, and Flavia Mulè. "TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon." International Journal of Molecular Sciences 21, no. 15 (July 29, 2020): 5403. http://dx.doi.org/10.3390/ijms21155403.
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The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon; (ii) to examine the effects of TRPM8 activation on colonic contractility; (iii) to characterize the mechanism of action. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used to analyze TRPM8 expression. The responses of human colon circular strips to different TRPM8 agonists [1-[Dialkyl-phosphinoyl]-alkane (DAPA) 2–5, 1-[Diisopropyl-phosphinoyl]-alkane (DIPA) 1–7, DIPA 1–8, DIPA 1–9, DIPA 1–10, and DIPA 1–12) were recorded using a vertical organ bath. The biomolecular analysis revealed gene and protein expression of TRPM8 in both mucosal and smooth muscle layers. All the agonists tested, except-DIPA 1–12, produced a concentration-dependent decrease in spontaneous contraction amplitude. The effect was significantly antagonized by 5-benzyloxytryptamine, a TRPM8 antagonist. The DIPA 1–8 agonist resulted in the most efficacious and potent activation among the tested molecules. The DIPA 1–8 effects were not affected by tetrodotoxin, a neural blocker, but they were significantly reduced by tetraethylammonium chloride, a non-selective blocker of K+ channels. Moreover, iberiotoxin, a blocker of the large-conductance Ca2+-dependent K+-channels, but not apamin, a blocker of small-conductance Ca2+-dependent K+ channels, significantly reduced the inhibitory DIPA 1–8 actions. The results of the present study demonstrated that TRPM8 receptors are also expressed in human distal colon in healthy conditions and that ligand-dependent TRPM8 activation is able to reduce the colonic spontaneous motility, probably by the opening of the large-conductance Ca2+-dependent K+-channels.
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Yamamura, Hisao, Shinya Ugawa, Takashi Ueda, Akimichi Morita, and Shoichi Shimada. "TRPM8 activation suppresses cellular viability in human melanoma." American Journal of Physiology-Cell Physiology 295, no. 2 (August 2008): C296—C301. http://dx.doi.org/10.1152/ajpcell.00499.2007.
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The transient receptor potential melastatin subfamily (TRPM), which is a mammalian homologue of cell death-regulated genes in Caenorhabditis elegans and Drosophila, has potential roles in the process of the cell cycle and regulation of Ca2+ signaling. Among this subfamily, TRPM8 (also known as Trp-p8) is a Ca2+-permeable channel that was originally identified as a prostate-specific gene upregulated in tumors. Here we showed that the TRPM8 channel was expressed in human melanoma G-361 cells, and activation of the channel produced sustainable Ca2+ influx. The application of menthol, an agonist for TRPM8 channel, elevated cytosolic Ca2+ concentration in a concentration-dependent manner with an EC50 value of 286 μM in melanoma cells. Menthol-induced responses were significantly abolished by the removal of external Ca2+. Moreover, inward currents at a holding potential of −60 mV in melanoma cells were markedly potentiated by the addition of 300 μM menthol. The most striking finding was that the viability of melanoma cells was dose-dependently depressed in the presence of menthol. These results reveal that a functional TRPM8 protein is expressed in human melanoma cells to involve the mechanism underlying tumor progression via the Ca2+ handling pathway, providing us with a novel target of drug development for malignant melanoma.
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Yu, Xiaoyun, Youtian Hu, Fei Ru, Marian Kollarik, Bradley J. Undem, and Shaoyong Yu. "TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 6 (March 15, 2015): G489—G496. http://dx.doi.org/10.1152/ajpgi.00336.2014.
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Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.
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De Caro, Carmen, Claudia Cristiano, Carmen Avagliano, Alessia Bertamino, Carmine Ostacolo, Pietro Campiglia, Isabel Gomez-Monterrey, et al. "Characterization of New TRPM8 Modulators in Pain Perception." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5544. http://dx.doi.org/10.3390/ijms20225544.
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Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.
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Johnson, Christopher D., Donal Melanaphy, Andrew Purse, Susan A. Stokesberry, Paula Dickson, and Alexander V. Zholos. "Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 6 (June 2009): H1868—H1877. http://dx.doi.org/10.1152/ajpheart.01112.2008.
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The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 μM). However, both menthol and another agonist icilin (50 μM) caused relaxation of vessels precontracted with KCl (60 mM) or the α-adrenoceptor agonist phenylephrine (2 μM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca2+-independent phospholipase A2 activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either Nω-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 μM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 μA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.
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Melanaphy, Donal, Christopher D. Johnson, Maxim V. Kustov, Conall A. Watson, Lyudmyla Borysova, Theodor V. Burdyga, and Alexander V. Zholos. "Ion channel mechanisms of rat tail artery contraction-relaxation by menthol involving, respectively, TRPM8 activation and L-type Ca2+ channel inhibition." American Journal of Physiology-Heart and Circulatory Physiology 311, no. 6 (December 1, 2016): H1416—H1430. http://dx.doi.org/10.1152/ajpheart.00222.2015.
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Transient receptor potential melastatin 8 (TRPM8) is the principal cold and menthol receptor channel. Characterized primarily for its cold-sensing role in sensory neurons, it is expressed and functional in several nonneuronal tissues, including vasculature. We previously demonstrated that menthol causes variable mechanical responses (vasoconstriction, vasodilatation, or biphasic reactions) in isolated arteries, depending on vascular tone. Here we aimed to dissect the specific ion channel mechanisms and corresponding Ca2+ signaling pathways underlying such complex responses to menthol and other TRPM8 ligands in rat tail artery myocytes using patch-clamp electrophysiology, confocal Ca2+ imaging, and ratiometric Ca2+ recording. Menthol (300 μM, a concentration typically used to induce TRPM8 currents) strongly inhibited L-type Ca2+ channel current (L- ICa) in isolated myocytes, especially its sustained component, most relevant for depolarization-induced vasoconstriction. In contraction studies, with nifedipine present (10 μM) to abolish L- ICa contribution to phenylephrine (PE)-induced vasoconstrictions of vascular rings, a marked increase in tone was observed with menthol, similar to resting (i.e., without α-adrenoceptor stimulation by PE) conditions, when L-type channels were mostly deactivated. Menthol-induced increases in PE-induced vasoconstrictions could be inhibited both by the TRPM8 antagonist AMTB (thus confirming the specific role of TRPM8) and by cyclopiazonic acid treatment to deplete Ca2+ stores, pointing to a major contribution of Ca2+ release from the sarcoplasmic reticulum in these contractile responses. Immunocytochemical analysis has indeed revealed colocalization of TRPM8 and InsP3 receptors. Moreover, menthol Ca2+ responses, which were somewhat reduced under Ca2+-free conditions, were strongly reduced by cyclopiazonic acid treatment to deplete Ca2+ store, whereas caffeine-induced Ca2+ responses were blunted in the presence of menthol. Finally, two other common TRPM8 agonists, WS-12 and icilin, also inhibited L- ICa. With respect to L- ICa inhibition, WS-12 is the most selective agonist. It augmented PE-induced contractions, whereas any secondary phase of vasorelaxation (as with menthol) was completely lacking. Thus TRPM8 channels are functionally active in rat tail artery myocytes and play a distinct direct stimulatory role in control of vascular tone. However, indirect effects of TRPM8 agonists, which are unrelated to TRPM8, are mediated by inhibition of L-type Ca2+ channels and largely obscure TRPM8-mediated vasoconstriction. These findings will promote our understanding of the vascular TRPM8 role, especially the well-known hypotensive effect of menthol, and may also have certain translational implications (e.g., in cardiovascular surgery, organ storage, transplantation, and Raynaud's phenomenon).
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Pan, Yuwei, Guoping Zhao, Zejian Cai, Fengguo Chen, Dandan Xu, Si Huang, Hai Lan, and Yi Tong. "Synergistic Effect of Ferulic Acid and Z-Ligustilide, Major Components ofA. sinensis, on Regulating Cold-Sensing Protein TRPM8 and TPRA1In Vitro." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/3160247.
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Angelica sinensishas been used to attenuate cold-induced cutaneous vasospasm syndrome, such as Raynaud’s disease and frostbite, in China for many years. Ferulic acid (PubChem CID: 445858) and Z-ligustilide (PubChem CID: 529865), two major components extracted fromAngelica sinensis, had been reported to inhibit vasoconstriction induced by vasoconstrictors. In this study, the pharmacological interaction in regulating cold-induced vascular smooth muscle cell contraction via cold-sensing protein TRPM8 and TRPA1 was analyzed between ferulic acid and Z-ligustilide. Pharmacological interaction on inhibiting[Ca2+]iinflux evoked by TRPM8 agonist WS-12 or TRPA1 agonist ASP 7663 as well as cold-induced upregulation of TRPM8 was determined using isobolographic analysis. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. Combination effect of two components in inhibiting RhoA activation and phosphorylation of MLC20induced by WS-12 or ASP 7663 was also being quantified. These findings suggest that the therapeutic effect ofAngelica sinensison cold-induced vasospasm may be partially attributed to combinational effect, via TRPM8 and TPRA1 way, between ferulic acid and Z-ligustilide.
Dissertations / Theses on the topic "TRPm8 agonist"
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Molina, Raya Lorena 1979. "Atención en la disfagia orofaríngea en la ancianidad y en pacientes con enfermedades neurológicas." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/664355.
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Resumen de la Tesis DoctoralIntroducción: La disfagia orofaríngea (DO) es muy prevalente en ancianos y pacientes con enfermedades neurológicas. No existe tratamiento farmacológico.Metodología: Se ha realizado una revisión sistemática, un ensayo clínico aleatorizado y un estudio de casos y controles. Resultados: el 66.7% de los estudios hablan de intervenciones en pacientes con DO secundaria a ICTUS. El 82.05% se realizó en entorno hospitalario y las enfermeras se mencionan en el 49.01% de los artículos. El mentol reduce el tiempo de cierre del vestíbulo laríngeo (VL) de 385 ± 136,2 ms a 340,8 ± 176,4 ms en la primera serie (P = 0,050) y 324,2 ± 130,1 en la segunda serie (P = 0,003). El mentol no cambió la prevalencia de residuos orofaríngeos ni la velocidad del bolo como la goma xantana (2; p<0.001; OR: 0.10 IC95%: 0.03 a 0.031). No hubo efectos adversos.Conclusiones: La DO secundaria a ICTUS es la etiología más identificada en la literatura. El cribado y la valoración son las intervenciones más frecuentes realizadas por los profesionales de enfermería. El tratamiento activo neuro-estimulador es el que modifica la biomecánica de la deglución y protege la vía aérea.AbstractIntroduction: Oropharyngeal dysphagia (OD) is a common disorder in elderly and in patients with neurological diseases. There is still not treatment available. Methods: A systematic review, a clinical trial and a case and controls study have been performed. Results: A 66.7% of the studies talk about interventions in patients with OD secondary to ICTUS. An 82.05% of those interventions were performed in a hospital setting and nurses played active role in the interventions in 49.01% of the articles. A 59.66% were experimental studies. Menthol reduced the laryngeal vestibule (LV) closing time from 385(SD:136,2)ms to 340,08(SD:176,4)ms (p=0,050) in the first, and 324,2ms(SD:130,1)ms in the second series (P=0,003). Menthol did not change the prevalence of oropharyngeal residues or bolus velocity as the xanthan-gum (OR: 0.10 IC95%: 0.03-0.031, 2; p<0.001). No adverse effects were detected.Conclusions: OD related to Stroke is the most frequent etiology identity in literature and screening and assessment are the most frequent interventions performed by nursing professionals. The active neuro-stimulator treatment modifies the biomechanics of swallowing, reduces the LV closing time and protect the airway
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Wrigley, Paul John. "Cold thermal processing in the spinal cord." 2006. http://hdl.handle.net/2123/1619.
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Doctor of Philosophy(PhD)Two recently identified transient receptor potential (TRP) channels, TRPM8 and TRPA1, have been proposed to play an important role in mammalian cool and cold peripheral sensory transduction. When expressed in cell-lines the cloned TRPM8 and TRPA1 receptors have distinct pharmacological and temperature response characteristics. Although these receptors are also transported to the central terminals of primary afferents, little is known about their centrally mediated actions. In this thesis, I use an in vitro electrophysiological approach to investigate the dorsal horn processing of cool afferent modalities and the role of TRP ion channels. The results of this thesis provide further information on thermal processing, indicate direction for further research and suggest possible therapeutic targets for the management of abnormal cold sensory processing. Initial experiments demonstrate that the cooling agents and known TRPM8 and TRPA1 agonists, menthol and icilin, inhibit primary afferent evoked excitatory postsynaptic currents (EPSCs) in rat spinal cord dorsal horn neurons. In addition, temperature reduction, menthol and icilin increase the frequency of miniature EPSCs without affecting amplitude distribution or kinetics. Little or no direct postsynaptic effect on dorsal horn neurons, GABAergic or glycinergic transmission was found. In combination, these observations demonstrate that temperature reduction, menthol and icilin act presynaptically to increase the probability of glutamate release from primary afferent fibres. Further examination of the changes in glutamatergic synaptic transmission induced by temperature reduction, menthol and icilin reveals a subset of neurons sensitive to innocuous cool (< 29 oC) and low concentrations of icilin (3-10 µM) which closely match the temperature activation and pharmacological profile of TRPM8. In addition, the majority of lamina I and II neurons displayed characteristics partly consistent with TRPA1-activation, including a concentration-dependent response to icilin and blockade by ruthenium red. The present experiments did not allow thermal characterisation of these TRPA1-like responses. Together these observations indicate that the effects of menthol and icilin on glutamatergic synaptic transmission in the superficial dorsal horn are mediated by TRPM8 and possibly by TRPA1. Examination of the anatomical location of neurons activated by temperature reduction, menthol, icilin and capsaicin allowed the central termination pattern of thermoreceptive primary afferent fibres with specific TRP-like response characteristics to be determined. TRPM8-like presynaptic activation was confined to a subpopulation of neurons located in lamina I and outer lamina II, while the majority of neurons throughout laminae I and II received inputs sensitive to menthol, high concentrations of icilin and capsaicin. These findings suggest that innocuous cool sensation projects to a specific subpopulation of superficial dorsal horn neurons unlike other modalities (mediated by TRPV1, possibly TRPA1 and other receptors), which non-selectively engage circuits within the entire superficial dorsal horn. No morphological specificity was identified for recovered neurons after electrophysiological characterisation. Finally, mu-opioids were shown to inhibit basal glutamatergic synaptic transmission as well as menthol- and icilin-induced transmission in the superficial dorsal horn. Of particular interest, delta-opioids selectively inhibited icilin-induced synaptic transmission within the same location. The selective effect of delta-opioids suggests a possible role in modulating receptors activated by icilin (TRPM8 and TRPA1). Overall, this thesis provides further evidence that TRPM8 is responsible for the transduction of innocuous cold sensation in mammals and is a potential therapeutic target in humans with cold hyperaesthesia secondary to abnormal thermal processing. The use of delta-opioid agonists warrants further investigation in cold hypersensitivity states and potentially other forms of pain.
Conference papers on the topic "TRPm8 agonist"
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Borodin, Evgeniy. "SEARCH FOR POTENTIAL LIGANDS FOR TRPM8 WITH THE HELP OF COMPUTER DESIGN." In XIV International Scientific Conference "System Analysis in Medicine". Far Eastern Scientific Center of Physiology and Pathology of Respiration, 2020. http://dx.doi.org/10.12737/conferencearticle_5fe01d9b2fdca3.97577371.
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A search was carried out for potential ligands to TRPM8 - a representative of the family of cationic channels with a transient receptor potential involved in the development of bronchial hypersensitivity and the occurrence of bronchospasm in response to low temperatures. We used a structural design and molecular docking using the autodock software package (http://autodock.scripps.edu/), which allows automated testing of many potential ligands for TRPM8. Docking was carried out with tyrosine 745 (Y745) amino acid residue as a critical residue for channel sensitivity to menthol, a classic TRPM8 agonist. The selection of potential candidates for the role of drugs intended for the treatment of bronchial cold hyperreactivity using in silico methods can be supplemented by testing their biological activity in vitro experiments with cell and tissue cultures and in vivo with experimental animals.
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Timkin, Pavel, E. Timofeev, A. Chupalov, and Evgeniy Borodin. "ANALYSIS AND SELECTION OF LIGANDS FOR TRPM8 USING HARD DOCKING AND MACHINE LEARNING." In XIV International Scientific Conference "System Analysis in Medicine". Far Eastern Scientific Center of Physiology and Pathology of Respiration, 2020. http://dx.doi.org/10.12737/conferencearticle_5fe01d9b233509.17835494.
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In this work, using the in-silico experiment modeling method, the receptor and its ligands were docked in order to obtain the data necessary to study the possibility of using machine learning and hard intermolecular docking methods to predict potential ligands for various receptors. The protein TRPM8 was chosen, which is a member of the TRP superfamily of proteins and its classic agonist menthol as a ligand. It is known that menthol is able to bind to tyrosine 745 of the B chain. To carry out all the manipulations, we used the Autodock software and a special set of graphic tools designed to work with in silico models of chemicals. As a result of all the manipulations, the menthol conformations were obtained that can bind to the active center of the TRPM8 receptor.
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Kanezaki, Masashi. "Olfactory stimulation of TRPM8 agonist lessen the perception of dyspnea induced by constant load exercise in never-smokers." In Annual Congress 2015. European Respiratory Society, 2015. http://dx.doi.org/10.1183/13993003.congress-2015.pa3719.
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Bonvini, SJ, MA Wortley, JJ Adcock, E. Dubuis, JA Bolaji, S. D’Sa, J. Ma, MA Birrell, and MG Belvisi. "T2 Oestrogen: an endogenous agonist for trpm3 triggered sensory nerve activation in the airway?" In British Thoracic Society Winter Meeting 2017, QEII Centre Broad Sanctuary Westminster London SW1P 3EE, 6 to 8 December 2017, Programme and Abstracts. BMJ Publishing Group Ltd and British Thoracic Society, 2017. http://dx.doi.org/10.1136/thoraxjnl-2017-210983.2.
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