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Journal articles on the topic 'TRPm8 agonist'

Author: Grafiati
Published: 4 June 2021
Last updated: 18 February 2022

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1

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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2

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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3

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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4

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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5

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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6

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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7

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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8

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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9

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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10

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.
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11

Houghton, Jack William, Guy Carpenter, Joachim Hans, Manuel Pesaro, Steven Lynham, and Gordon Proctor. "Agonists of Orally Expressed TRP Channels Stimulate Salivary Secretion and Modify the Salivary Proteome." Molecular & Cellular Proteomics 19, no. 10 (July 10, 2020): 1664–76. http://dx.doi.org/10.1074/mcp.ra120.002174.

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Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.
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12

Feketa, Viktor V., Adithya Balasubramanian, Christopher M. Flores, Mark R. Player, and Sean P. Marrelli. "Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 9 (November 1, 2013): R1040—R1050. http://dx.doi.org/10.1152/ajpregu.00296.2013.

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Mild decrease of core temperature (32–34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 ± 1.8; compound 5: 23.8 ± 2.0; TRPM8 KO: 19.7 ± 1.9 V·s/min), tachycardia (ΔHR = 124 ± 31; 121 ± 13; 121 ± 31 beats/min) and drop in core temperature (−3.6 ± 0.1; −3.4 ± 0.4; −3.6 ± 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 ± 3.0 vs. DHC: 5.1 ± 2.0 V·s/min), tachycardia (ΔHR = 204 ± 25 vs. 3 ± 35 beats/min) and produced a profound drop in core temperature (−2.2 ± 0.6 vs. −8.9 ± 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia.
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13

Yang, Jee, Edward Wei, Seong Kim, and Kyung Yoon. "TRPM8 Channels and Dry Eye." Pharmaceuticals 11, no. 4 (November 15, 2018): 125. http://dx.doi.org/10.3390/ph11040125.

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Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist.
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14

Kullmann, F. Aura, M. A. Shah, L. A. Birder, and W. C. de Groat. "Functional TRP and ASIC-like channels in cultured urothelial cells from the rat." American Journal of Physiology-Renal Physiology 296, no. 4 (April 2009): F892—F901. http://dx.doi.org/10.1152/ajprenal.90718.2008.

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Transient receptor potential (TRP) and acid-sensing ion channels (ASIC) are molecular detectors of chemical, mechanical, thermal, and nociceptive stimuli in sensory neurons. They have been identified in the urothelium, a tissue considered part of bladder sensory pathways, where they might play a role in bladder function. This study investigated functional properties of TRP and ASIC channels in cultured urothelial cells from the rat using patch-clamp and fura 2 Ca2+ imaging techniques. The TRPV4 agonist 4α-phorbol-12,13 didecanoate (4α-PDD; 1–5 μM) and the TRPA1/TRPM8 agonist icilin (50–100 μM) elicited transient currents in a high percentage of cells (>70%). 4α-PDD responses were suppressed by the TRPV4 antagonist HC-010961 (10 μM). The TRPV1 agonist capsaicin (1–100 μM) and the TRPA1/TRPM8 agonist menthol (5–200 μM) elicited transient currents in a moderate percentage of cells (∼25%). All of these agonists increased intracellular calcium concentration ([Ca2+]i). Most cells responded to more than one TRP agonist (e.g., capsaicin and 4α-PDD), indicating coexpression of different TRP channels. In the presence of the TRPV1 antagonist capsazepine (10 μM), changes in pH induced by HCl elicited ionic currents (pH 5.5) and increased [Ca2+]i (pH 6.5) in ∼50% of cells. Changes in pH using acetic acid (pH 5.5) elicited biphasic-like currents. Responses induced by acid were sensitive to amiloride (10 μM). In summary, urothelial cells express multiple TRP and ASIC channels, whose activation elicits ionic currents and Ca2+ influx. These “neuron-like” properties might be involved in transmitter release, such as ATP, that can act on afferent nerves or smooth muscle to modulate their responses to different stimuli.
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15

Yoon, Hyeon Jeong, Jonghwa Kim, Jee Myung Yang, Edward T. Wei, Seong Jin Kim, and Kyung Chul Yoon. "Topical TRPM8 Agonist for Relieving Neuropathic Ocular Pain in Patients with Dry Eye: A Pilot Study." Journal of Clinical Medicine 10, no. 2 (January 12, 2021): 250. http://dx.doi.org/10.3390/jcm10020250.

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Background: Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP. Methods: We conducted a prospective pilot study of 15 patients with DE-associated NOP. These patients applied topical C3 to their eyelid, 4 times/day for 1 month. The patients underwent clinical examinations. They also completed the Ocular Pain Assessment Survey (OPAS), which is a validated questionnaire for NOP, at baseline, 1 week, and 1 month after treatment. Result: At 1 week, the OPAS scores of eye pain intensity, quality of life (driving/watching TV, general activity, sleep, and enjoying life/relations with other people), and associated factors (burning sensation, light sensitivity, and tearing) improved. The total OPAS scores of eye pain intensity, quality of life, and associated factors remained improved at 1 month. The Schirmer test scores also improved at 1 month. Conclusion: TRPM8 agonist (C3) could be a novel agent for treating patients with DE-associated NOP who are unresponsive to conventional treatments.
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16

Typolt, Oliver, and Davide Filingeri. "Evidence for the involvement of peripheral cold-sensitive TRPM8 channels in human cutaneous hygrosensation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 3 (March 1, 2020): R579—R589. http://dx.doi.org/10.1152/ajpregu.00332.2019.

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In contrast to other species, humans are believed to lack hygroreceptors for sensing skin wetness. Yet, the molecular basis of human hygrosensation is currently unknown, and it remains unclear whether we possess a receptor-mediated sensing mechanism for skin wetness. The aim of this study was to assess the role of the cutaneous cold-sensitive transient receptor potential melastatin-8 (TRPM8) channel as a molecular mediator of human hygrosensation. To this end, we exploited both the thermal and chemical activation of TRPM8-expressing cutaneous Aδ cold thermoreceptors, and we assessed wetness sensing in healthy young men in response to 1) dry skin cooling in the TRPM8 range of thermosensitivity and 2) application of the TRPM8 agonist menthol. Our results indicate that 1) independently of contact with moisture, a cold-dry stimulus in the TRPM8 range of activation induced wetness perceptions across 12 different body regions and those wetness perceptions varied across the body following regional differences in cold sensitivity; and 2) independently of skin cooling, menthol-induced stimulation of TRPM8 triggered wetness perceptions that were greater than those induced by physical dry cooling and by contact with an aqueous cream containing actual moisture. For the first time, we show that the cutaneous cold-sensing TRPM8 channel plays the dual role of cold and wetness sensor in human skin and that this ion channel is a peripheral mediator of human skin wetness perception.
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De Petrocellis, Luciano, Giorgio Ortar, Aniello Schiano Moriello, Eric M. Serum, and David B. Rusterholz. "Structure–activity relationships of the prototypical TRPM8 agonist icilin." Bioorganic & Medicinal Chemistry Letters 25, no. 11 (June 2015): 2285–90. http://dx.doi.org/10.1016/j.bmcl.2015.04.032.

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Zhang, Lei, Sarahlouise Jones, Kate Brody, Marcello Costa, and Simon J. H. Brookes. "Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 6 (June 2004): G983—G991. http://dx.doi.org/10.1152/ajpgi.00441.2003.

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A number of transient receptor potential (TRP) channels has recently been shown to mediate cutaneous thermosensitivity. Sensitivity to warm and cool stimuli has been demonstrated in both human and animal gastrointestinal tract; however, the molecular mechanisms that underlie this have not been determined. Vagal afferent neurons with cell bodies in the nodose ganglion are known to mediate nonnociceptive sensation from the upper gut. In this study, isolated cultured nodose ganglion from the mouse neurons showed changes in cytoplasmic-free Ca2+concentrations over a range of temperatures, as well as to icilin (a TRPM8 and TRPN1 agonist) and capsaicin (a TRPV1 agonist). RT-PCR was used to show the presence of six temperature-sensitive TRP channel transcripts (TRPV1–4, TRPN1, and TRPM8) in whole nodose ganglia. In addition, RT-PCR of single nodose cell bodies, which had been retrogradely labeled from the upper gut, detected transcripts for TRPV1, TRPV2, TRPV4, TRPN1, and TRPM8 in a proportion of cells. Immunohistochemical labeling detected TRPV1 and TRPV2 proteins in nodose ganglia. The presence of TRP channel transcripts and proteins was also detected in cells within several regions of the gastrointestinal tract. Our results reveal that TRP channels are present in subsets of vagal afferent neurons that project to the stomach and may confer temperature sensitivity on these cells.
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Chen, Gui-Lan, Ming Lei, Lu-Ping Zhou, Bo Zeng, and Fangdong Zou. "Borneol Is a TRPM8 Agonist that Increases Ocular Surface Wetness." PLOS ONE 11, no. 7 (July 22, 2016): e0158868. http://dx.doi.org/10.1371/journal.pone.0158868.

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Hussain, Zahir, Lusine Demirkhanyan, Swapna Asuthkar, and Eleonora Zakharian. "Testosterone is a Highly Potent and Specific Agonist of TRPM8." Biophysical Journal 110, no. 3 (February 2016): 613a. http://dx.doi.org/10.1016/j.bpj.2015.11.3270.

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21

Plevkova, J., M. Kollarik, I. Poliacek, M. Brozmanova, L. Surdenikova, M. Tatar, N. Mori, and B. J. Canning. "The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol." Journal of Applied Physiology 115, no. 2 (July 15, 2013): 268–74. http://dx.doi.org/10.1152/japplphysiol.01144.2012.

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The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (−)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.
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22

Pfanzagl, Beatrix, Roswitha Pfragner, and Erika Jensen-Jarolim. "The Transient Receptor Potential Vanilloid 4 Agonist RN-1747 Inhibits the Calcium Response to Histamine." Pharmacology 104, no. 3-4 (2019): 166–72. http://dx.doi.org/10.1159/000501144.

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Background: Sensitization of transient receptor potential (TRP) cation channels probably contributes to intestinal hypersensitivity, a hallmark of gastrointestinal disorders. Histamine acting via histamine 1 receptor (H1R) to open TRP cation channels might also be involved. Method: The enterochromaffin cell line P-STS, responsive to histamine via H1R, was used as model to study possible synergism between histamine and TRP vanilloid 4 (TRPV4) pathways. Results: The TRPV4 antagonist RN-1734, but not HC-067047, inhibited the cytoplasmic calcium response to histamine in P-STS cells. However, also pre-incubation with the TRPV4 agonist RN-1747 strongly inhibited the calcium response to histamine in P-STS as well as HeLa cells. This inhibitory effect of RN-1747 was not due to its known TRP melastatin 8 (TRPM8) antagonism, as the TRPM8 antagonist RQ-00203078 showed no significant effect on the histamine-induced calcium response of P-STS or HeLa cells. Conclusion: The TRPV4 agonist RN-1747, and possibly also the structurally similar TRPV4 antagonist RN-1734, should be used with caution because of yet unidentified interference with histamine signaling via H1R.
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23

Cooper, Skylar Y., Austin T. Akers, Velvet Blair Journigan, and Brandon J. Henderson. "Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior." Molecules 26, no. 16 (August 7, 2021): 4793. http://dx.doi.org/10.3390/molecules26164793.

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The popular tobacco and e-cigarette chemical flavorant (−)-menthol acts as a nonselective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs), and contributes to multiple physiological effects that exacerbates nicotine addiction-related behavior. Menthol is classically known as a TRPM8 agonist; therefore, some have postulated that TRPM8 antagonists may be potential candidates for novel nicotine cessation pharmacotherapies. Here, we examine a novel class of TRPM8 antagonists for their ability to alter nicotine reward-related behavior in a mouse model of conditioned place preference. We found that these novel ligands enhanced nicotine reward-related behavior in a mouse model of conditioned place preference. To gain an understanding of the potential mechanism, we examined these ligands on mouse α4β2 nAChRs transiently transfected into neuroblastoma-2a cells. Using calcium flux assays, we determined that these ligands act as positive modulators (PMs) on α4β2 nAChRs. Due to α4β2 nAChRs’ important role in nicotine dependence, as well as various neurological disorders including Parkinson’s disease, the identification of these ligands as α4β2 nAChR PMs is an important finding, and they may serve as novel molecular tools for future nAChR-related investigations.
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24

Zanotto, Karen L., Austin W. Merrill, Mirela Iodi Carstens, and E. Carstens. "Neurons in Superficial Trigeminal Subnucleus Caudalis Responsive to Oral Cooling, Menthol, and Other Irritant Stimuli." Journal of Neurophysiology 97, no. 2 (February 2007): 966–78. http://dx.doi.org/10.1152/jn.00996.2006.

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The recent discoveries of cold-sensitive transient receptor potential (TRP) channels prompted us to investigate the responses of neurons in trigeminal subnucleus caudalis (Vc) to intraoral cooling and agonists of TRPM8 and TRPA1. Single units responsive to lingual cooling were recorded in superficial laminae of Vc in thiopental-anesthetized rats. All units responded to noxious heat and 88% responded to menthol. Responses increased with menthol concentration from 0.1 to 1% (6.4–64 mM) and plateaued at 10% (640 mM). Noxious cold-evoked responses were significantly enhanced after menthol in a concentration-dependent manner. Constant-flow application of 1% menthol elicited a phasic discharge that adapted over 2–8 min and significantly enhanced subsequent cold-evoked but not heat-evoked responses; vehicle (10% ethanol) was ineffective. Reapplication of menthol 15 min later elicited a significantly reduced response (self-desensitization). Vc units were similarly excited phasically by 1% menthol dissolved in 40% ethanol. The 40% ethanol briefly excited Vc units during the first minute and reduced subsequent responses to noxious heat and cold while exhibiting neither self-desensitization nor cross-desensitization to menthol. Menthol cross-desensitized Vc responses to 40% ethanol. Most menthol-responsive units also responded to the TRPA1 agonists cinnamaldehyde and mustard oil, and the TRPV1 agonist capsaicin. Units in superficial Vc receive convergent input from primary afferents that express TRPM8, TRPA1, and/or TRPV1 channels, either directly or indirectly via intersubnuclear pathways. The convergent nature of these units suggests a general role in signaling noxious stimuli.
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25

Khare, Pragyanshu, Aakriti Chauhan, Vibhu Kumar, Jasleen Kaur, Neha Mahajan, Vijay Kumar, Adam Gesing, Kanwaljit Chopra, Kanthi Kiran Kondepudi, and Mahendra Bishnoi. "Bioavailable Menthol (Transient Receptor Potential Melastatin-8 Agonist) Induces Energy Expending Phenotype in Differentiating Adipocytes." Cells 8, no. 5 (April 26, 2019): 383. http://dx.doi.org/10.3390/cells8050383.

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Recent evidence supports the role of menthol, a TRPM8 agonist, in enhanced energy expenditure, thermogenesis and BAT-like activity in classical WAT depots in a TRPM8 dependent and independent manner. The present study was designed to analyse whether oral and topical administration of menthol is bioavailable at subcutaneous adipose tissue and is sufficient to directlyinduce desired energy expenditure effects. GC-FID was performed to study menthol bioavailability in serum and subcutaneous white adipose tissue following oral and topical administration. Further, 3T3L1 adipocytes were treated with bioavailable menthol doses and different parameters (lipid accumulation, “browning/brite” and energy expenditure gene expression, metal analysis, mitochondrial complex’s gene expression) were studied. No difference was observed in serum levels but significant difference was seen in the menthol concentration on subcutaneous adipose tissues after oral and topical application. Menthol administration at bioavailable doses significantly increased “browning/brite” and energy expenditure phenotype, enhanced mitochondrial activity related gene expression, increased metal concentration during adipogenesis but did not alter the lipid accumulation as well as acute experiments were performed with lower dose of menthol on mature adipocytes In conclusion, the present study provides evidence that bioavailable menthol after single oral and topical administration is sufficient to induce “brite” phenotype in subcutaneous adipose tissue However, critical dose characterization for its clinical utility is required.
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Shirai, Tomohiro, Kentaro Kumihashi, Mitsuyoshi Sakasai, Hiroshi Kusuoku, Yusuke Shibuya, and Atsushi Ohuchi. "Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound." ACS Medicinal Chemistry Letters 8, no. 7 (June 5, 2017): 715–19. http://dx.doi.org/10.1021/acsmedchemlett.7b00104.

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27

Toro, Carlos A., Stephanie Eger, Luis Veliz, Pamela Sotelo-Hitschfeld, Deny Cabezas, Maite A. Castro, Katharina Zimmermann, and Sebastian Brauchi. "Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8." Journal of Neuroscience 35, no. 2 (January 14, 2015): 571–82. http://dx.doi.org/10.1523/jneurosci.3820-13.2015.

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28

Zhang, Xiao-Bing, Peng Jiang, Neng Gong, Xiao-Ling Hu, Da Fei, Zhi-Qi Xiong, Lin Xu, and Tian-Le Xu. "A-Type GABA Receptor as a Central Target of TRPM8 Agonist Menthol." PLoS ONE 3, no. 10 (October 13, 2008): e3386. http://dx.doi.org/10.1371/journal.pone.0003386.

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29

Dong, Peijian, Yan Huang, Qinxian Wei, Xinyu Wang, Chunli Liu, and TakFung Wei. "A TRPM8 Agonist Ax-8 Inhibits Capsaicin-Induced Cough in Guinea Pig." Chest 149, no. 4 (April 2016): A545. http://dx.doi.org/10.1016/j.chest.2016.02.569.

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30

Borgonovo, Gigliola, Luciano De Petrocellis, Aniello Schiano Moriello, Simona Bertoli, Alessandro Leone, Alberto Battezzati, Stefania Mazzini, and Angela Bassoli. "Moringin, A Stable Isothiocyanate from Moringa oleifera, Activates the Somatosensory and Pain Receptor TRPA1 Channel In Vitro." Molecules 25, no. 4 (February 22, 2020): 976. http://dx.doi.org/10.3390/molecules25040976.

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Moringa oleifera Lam. is a tropical plant widely used in traditional medicines and as a food supplement. It is characterized by the presence of glucosinolates and isothiocyanates; the stable isothiocyanate 4-[(α-l-rhamnosyloxy)benzyl]isothiocyanate (moringin) has been widely studied for its bioactivity as hypoglycemic, antimicrobial, anticancer and in particular for its involvement in nociception and neurogenic pain. Moringa extracts and pure moringin were submitted to in vitro assays with the somatosensory TRPA1 ion channel, proving that moringin is a potent and effective agonist of this receptor involved in nociceptive function and pain states. Moringin do not activate or activates very weakly the vanilloids somatosensory channels TRPV1,2,3 and 4, and the melastatin cooling receptor TRPM8. The comparison of moringin’s activity with other known agonists of natural origin is also discussed.
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31

Blackshaw, L. Ashley, Stuart M. Brierley, Andrea M. Harrington, and Patrick A. Hughes. "TRP Channels in Visceral Pain." Open Pain Journal 6, no. 1 (March 8, 2013): 23–30. http://dx.doi.org/10.2174/1876386301306010023.

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Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.
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32

Han, J., H. Choi, and S. Kim. "Topical TRPM8 Agonist (Icilin) Relieved Vulva Pruritus Originating From Lichen Sclerosus et Atrophicus." Acta Dermato Venereologica 92, no. 5 (2012): 561–62. http://dx.doi.org/10.2340/00015555-1244.

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33

Takaishi, Masayuki, Fumitaka Fujita, Kunitoshi Uchida, Satoshi Yamamoto, Maki Sawada (Shimizu), Chihiro Hatai (Uotsu), Mayumi Shimizu, and Makoto Tominaga. "1,8-Cineole, a TRPM8 Agonist, is a Novel Natural Antagonist of Human TRPA1." Molecular Pain 8 (January 2012): 1744–8069. http://dx.doi.org/10.1186/1744-8069-8-86.

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34

Rawls, Scott M., Teresa Gomez, Zhe Ding, and Robert B. Raffa. "Differential behavioral effect of the TRPM8/TRPA1 channel agonist icilin (AG-3-5)." European Journal of Pharmacology 575, no. 1-3 (December 2007): 103–4. http://dx.doi.org/10.1016/j.ejphar.2007.07.060.

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35

Poulson, Sandra J., Ahmed Aldarraji, Iqra I. Arain, Natalia Dziekonski, Keza Motlana, Rachel Riley, Melissa M. Holmes, and Loren J. Martin. "Naked mole-rats lack cold sensitivity before and after nerve injury." Molecular Pain 16 (January 2020): 174480692095510. http://dx.doi.org/10.1177/1744806920955103.

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Neuropathic pain is a chronic disease state resulting from injury to the nervous system. This type of pain often responds poorly to standard treatments and occasionally may get worse instead of better over time. Patients who experience neuropathic pain report sensitivity to cold and mechanical stimuli. Since the nociceptive system of African naked mole-rats contains unique adaptations that result in insensitivity to some pain types, we investigated whether naked mole-rats may be resilient to sensitivity following nerve injury. Using the spared nerve injury model of neuropathic pain, we showed that sensitivity to mechanical stimuli developed similarly in mice and naked mole-rats. However, naked mole-rats lacked sensitivity to mild cold stimulation after nerve injury, while mice developed robust cold sensitivity. We pursued this response deficit by testing behavior to activators of transient receptor potential (TRP) receptors involved in detecting cold in naïve animals. Following mustard oil, a TRPA1 activator, naked mole-rats responded similarly to mice. Conversely, icilin, a TRPM8 agonist, did not evoke pain behavior in naked mole-rats when compared with mice. Finally, we used RNAscope to probe for TRPA1 and TRPM8 messenger RNA expression in dorsal root ganglia of both species. We found increased TRPA1 messenger RNA, but decreased TRPM8 punctae in naked mole-rats when compared with mice. Our findings likely reflect species differences due to evolutionary environmental responses that are not easily explained by differences in receptor expression between the species.
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36

Kurose, Masayuki, and Ian D. Meng. "Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells." Journal of Neurophysiology 110, no. 2 (July 15, 2013): 495–504. http://dx.doi.org/10.1152/jn.00222.2013.

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Dry eye syndrome is a painful condition caused by inadequate or altered tear film on the ocular surface. Primary afferent cool cells innervating the cornea regulate the ocular fluid status by increasing reflex tearing in response to evaporative cooling and hyperosmicity. It has been proposed that activation of corneal cool cells via a transient receptor potential melastatin 8 (TRPM8) channel agonist may represent a potential therapeutic intervention to treat dry eye. This study examined the effect of dry eye on the response properties of corneal cool cells and the ability of the TRPM8 agonist menthol to modify these properties. A unilateral dry eye condition was created in rats by removing the left lacrimal gland. Lacrimal gland removal reduced tears in the dry eye to 35% compared with the contralateral eye and increased the number of spontaneous blinks in the dry eye by over 300%. Extracellular single-unit recordings were performed 8–10 wk following surgery in the trigeminal ganglion of dry eye animals and age-matched controls. Responses of corneal cool cells to cooling were examined after the application of menthol (10 μM–1.0 mM) to the ocular surface. The peak frequency of discharge to cooling was higher and the cooling threshold was warmer in dry eye animals compared with controls. The dry condition also altered the neuronal sensitivity to menthol, causing desensitization to cold-evoked responses at concentrations that produced facilitation in control animals. The menthol-induced desensitization of corneal cool cells would likely result in reduced tearing, a deleterious effect in individuals with dry eye.
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37

Hatta, Azusa, Masayuki Kurose, Cara Sullivan, Keiichiro Okamoto, Noritaka Fujii, Kensuke Yamamura, and Ian D. Meng. "Dry eye sensitizes cool cells to capsaicin-induced changes in activity via TRPV1." Journal of Neurophysiology 121, no. 6 (June 1, 2019): 2191–201. http://dx.doi.org/10.1152/jn.00126.2018.

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Corneal cool cells are sensitive to the ocular fluid status of the corneal surface and may be responsible for the regulation of basal tear production. Previously, we have shown that dry eye, induced by lacrimal gland excision (LGE) in rats, sensitized corneal cool cells to the transient receptor potential melastatin 8 (TRPM8) agonist menthol and to cool stimulation. In the present study, we examined the effect of dry eye on the sensitivity of cool cells to the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin. Single-unit recordings in the trigeminal ganglion were performed 7–10 days after LGE. At a concentration of 0.3 μM, capsaicin did not affect ongoing or cool-evoked activity in control animals yet facilitated ongoing activity and suppressed cool-evoked activity in LGE animals. At higher concentrations (3 μM), capsaicin continued to facilitate ongoing activity in LGE animals but suppressed ongoing activity in control animals. Higher concentrations of capsaicin also suppressed cool-evoked activity in both groups of animals, with an overall greater effect in LGE animals. In addition to altering cool-evoked activity, capsaicin enhanced the sensitivity of cool cells to heat in LGE animals. Capsaicin-induced changes were prevented by the application of the TRPV1 antagonist capsazepine. With the use of fluorescent in situ hybridization, TRPV1 and TRPM8 expression was examined in retrograde tracer-identified corneal neurons. The coexpression of TRPV1 and TRPM8 in corneal neurons was significantly greater in LGE-treated animals when compared with sham controls. These results indicate that LGE-induced dry eye increases TRPV1-mediated responses in corneal cool cells at least in part through the increased expression of TRPV1. NEW & NOTEWORTHY Corneal cool cells are known to detect drying of the ocular surface. Our study is the first to report that dry eye induced alterations in cool cell response properties, including the increased responsiveness to noxious heat and activation by capsaicin. Along with the changes in cell response properties, it is possible these neurons also function differently in dry eye, relaying information related to the perception of ocular irritation in addition to regulating tearing and blinking.
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38

Kozyreva, T. V., V. P. Kozaruk, E. Ya Tkachenko, and G. M. Khramova. "Agonist of TRPM8 channel, menthol, facilitates the initiation of thermoregulatory responses to external cooling." Journal of Thermal Biology 35, no. 8 (December 2010): 428–34. http://dx.doi.org/10.1016/j.jtherbio.2010.09.004.

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39

Wei, Edward T. "Improving brain power by applying a cool TRPM8 receptor agonist to the eyelid margin." Medical Hypotheses 142 (September 2020): 109747. http://dx.doi.org/10.1016/j.mehy.2020.109747.

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40

Duncan, David, Frances Stewart, Mark Frohlich, and David Urdal. "PRECLINICAL EVALUATION OF THE TRPM8 ION CHANNEL AGONIST D-3263 FOR BENIGN PROSTATIC HYPERPLASIA." Journal of Urology 181, no. 4S (April 2009): 503. http://dx.doi.org/10.1016/s0022-5347(09)61422-1.

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41

Fallon, M. T., D. J. Storey, A. Krishan, C. J. Weir, R. Mitchell, S. M. Fleetwood-Walker, A. C. Scott, and L. A. Colvin. "Cancer treatment-related neuropathic pain: proof of concept study with menthol—a TRPM8 agonist." Supportive Care in Cancer 23, no. 9 (February 15, 2015): 2769–77. http://dx.doi.org/10.1007/s00520-015-2642-8.

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42

Banke, T. G., S. R. Chaplan, and A. D. Wickenden. "Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation." American Journal of Physiology-Cell Physiology 298, no. 6 (June 2010): C1457—C1468. http://dx.doi.org/10.1152/ajpcell.00489.2009.

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TRPA1 is a nonselective cation channel belonging to the transient receptor potential (TRP) family that is expressed in peripheral sensory neurons and may play important roles in pain perception and inflammation. We found that agonist stimulation of TRPA1, along with other members of the TRP family (TRPV1–4 and TRPM8), can induce the appearance of a large pore permeable to large organic cations such as Yo-Pro (YP) and N-methyl-d-glucamine, in an agonist and divalent cation-dependent manner. YP uptake was not inhibited by a panel of putative gap junction/pannexin blockers, suggesting that gap junction proteins are not required in this process. Our data suggest that changes in the TRP channel selectivity filter itself result in a progressive but reversible pore dilation process, a process that is under strong regulation by external calcium ions. Our data suggest that calcium plays a novel role in setting the amount of time TRPA1 channels spend in a dilated state providing a mechanism that may limit sensory neuron activation by painful or irritating substances.
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43

Patel, Ryan, Leonor Gonçalves, Mathew Leveridge, Stephen R. Mack, Alan Hendrick, Nicola L. Brice, and Anthony H. Dickenson. "Anti-hyperalgesic effects of a novel TRPM8 agonist in neuropathic rats: A comparison with topical menthol." Pain 155, no. 10 (October 2014): 2097–107. http://dx.doi.org/10.1016/j.pain.2014.07.022.

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44

Teliban, Alina, Fabian Bartsch, Marek Struck, Ralf Baron, and Wilfrid Jänig. "Responses of intact and injured sural nerve fibers to cooling and menthol." Journal of Neurophysiology 111, no. 10 (May 15, 2014): 2071–83. http://dx.doi.org/10.1152/jn.00287.2013.

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Intact and injured cutaneous C-fibers in the rat sural nerve are cold sensitive, heat sensitive, and/or mechanosensitive. Cold-sensitive fibers are either low-threshold type 1 cold sensitive or high-threshold type 2 cold sensitive. The hypothesis was tested, in intact and injured afferent nerve fibers, that low-threshold cold-sensitive afferent nerve fibers are activated by the transient receptor potential melastatin 8 (TRPM8) agonist menthol, whereas high-threshold cold-sensitive C-fibers and cold-insensitive afferent nerve fibers are menthol insensitive. In anesthetized rats, activity was recorded from afferent nerve fibers in strands isolated from the sural nerve, which was either intact or crushed 6–12 days before the experiment distal to the recording site. In all, 77 functionally identified afferent C-fibers (30 intact fibers, 47 injured fibers) and 34 functionally characterized A-fibers (11 intact fibers, 23 injured fibers) were tested for their responses to menthol applied to their receptive fields either in the skin (10 or 20%) or in the nerve (4 or 8 mM). Menthol activated all intact ( n = 12) and 90% of injured ( n = 20/22) type 1 cold-sensitive C-fibers; it activated no intact type 2 cold-sensitive C-fibers ( n = 7) and 1/11 injured type 2 cold-sensitive C-fibers. Neither intact nor injured heat- and/or mechanosensitive cold-insensitive C-fibers ( n = 25) and almost no A-fibers ( n = 2/34) were activated by menthol. These results strongly argue that cutaneous type 1 cold-sensitive afferent fibers are nonnociceptive cold fibers that use the TRPM8 transduction channel.
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Misery, L., A. Santerre, A. Batardière, N. Hornez, A. S. Nedelec, F. Le Caër, P. Bourgeois, F. Huet, and G. Neufang. "Real-life study of anti-itching effects of a cream containing menthoxypropanediol, a TRPM8 agonist, in atopic dermatitis patients." Journal of the European Academy of Dermatology and Venereology 33, no. 2 (August 20, 2018): e67-e69. http://dx.doi.org/10.1111/jdv.15199.

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46

Ständer, S., M. Augustin, D. Roggenkamp, C. Blome, T. Heitkemper, A. C. Worthmann, and G. Neufang. "Novel TRPM8 agonist cooling compound against chronic itch: results from a randomized, double-blind, controlled, pilot study in dry skin." Journal of the European Academy of Dermatology and Venereology 31, no. 6 (December 7, 2016): 1064–68. http://dx.doi.org/10.1111/jdv.14041.

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47

Rodríguez-Arévalo, Sergio, Eugènia Pujol, Sònia Abás, Carles Galdeano, Carmen Escolano, and Santiago Vázquez. "Synthesis, Characterization and HPLC Analysis of the (1S,2S,5R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512." Molecules 26, no. 4 (February 9, 2021): 906. http://dx.doi.org/10.3390/molecules26040906.

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Abstract:
AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.
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48

Kawasaki, Hiroki, Kotaro Mizuta, Tsugumi Fujita, Masanari Inoue, Chang-Yu Jiang, Toshiharu Yasaka, Satoko Uemura, Hai-Yuan Yue, Liu Yang, and Eiichi Kumamoto. "Inhibition by TRPM8 agonist menthol and its related substances with p-menthane base of compound action potentials in frog sciatic nerves." Neuroscience Research 71 (September 2011): e315. http://dx.doi.org/10.1016/j.neures.2011.07.1375.

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49

Tolcher, A., A. Patnaik, K. Papadopoulos, T. Mays, T. Stephan, D. J. Humble, M. W. Frohlich, and R. B. Sims. "376 Preliminary results from a Phase 1 study of D-3263 HCl, a TRPM8 calcium channel agonist, in patients with advanced cancer." European Journal of Cancer Supplements 8, no. 7 (November 2010): 119. http://dx.doi.org/10.1016/s1359-6349(10)72083-8.

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50

Tamamoto-Mochizuki, Chie, K. Marcia Murphy, and Thierry Olivry. "Pilot evaluation of the antipruritic efficacy of a topical transient receptor potential melastatin subfamily 8 (TRPM8) agonist in dogs with atopic dermatitis and pedal pruritus." Veterinary Dermatology 29, no. 1 (September 26, 2017): 29—e14. http://dx.doi.org/10.1111/vde.12486.

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