Analgesia Mediated by the TRPM8 Cold Receptor in Chronic Neuropathic Pain

Proudfoot, Clare J.; Garry, Emer M.; Cottrell, David F.; Rosie, Roberta; Anderson, Heather; Robertson, Darren; Fleetwood-Walker, Susan M.; Mitchell, Rory

doi:10.1016/j.cub.2006.07.061

Cited by 380 publications

(358 citation statements)

References 61 publications

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“…Although TRPM8 is restricted to a small subset of sensory neurons, it is critical in most aspects of cold sensation (Bautista et al, 2007;Colburn et al, 2007;Dhaka et al, 2007). Even more notable, the channel is key in the analgesia provided by moderate cooling and modest doses of cooling compounds (Proudfoot et al, 2006;Dhaka et al, 2007). Thus, both in vitro and in vivo data suggests a single molecule, expressed on a small number of sensory axons, mediates many aspects of sensory signaling depending on the quality of the stimulus and tissue state.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking TRPM8 are deficient in detecting innocuous cool temperatures and exhibit a partially defective phenotype in responding to noxious cold (Bautista et al, 2007;Colburn et al, 2007;Dhaka et al, 2007). Moreover, activation of TRPM8 is required for the analgesia provided by cooling and cooling compounds (Proudfoot et al, 2006;Dhaka et al, 2007) and, paradoxically, is essential in injuryevoked hypersensitivity to cold (Colburn et al, 2007;Dhaka et al, 2007). Thus, TRPM8 plays a principal role in the perception of cold temperatures and raises the question: how can a single receptor be involved in multiple, and in some cases antagonistic (pain vs analgesia), aspects of sensory signaling?…”

Section: Introductionmentioning

confidence: 99%

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Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Takashima¹,

Daniels²,

Knowlton³

et al. 2007

J. Neurosci.

195

214

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Sensory nerves detect an extensive array of somatosensory stimuli, including environmental temperatures. Despite activating only a small cohort of sensory neurons, cold temperatures generate a variety of distinct sensations that range from pleasantly cool to painfully aching, prickling, and burning. Psychophysical and functional data show that cold responses are mediated by both C-and A␦-fibers with separate peripheral receptive zones, each of which likely provides one or more of these distinct cold sensations. With this diversity in the neural basis for cold, it is remarkable that the majority of cold responses in vivo are dependent on the cold and menthol receptor transient receptor potential melastatin 8 (TRPM8). TRPM8-null mice are deficient in temperature discrimination, detection of noxious cold temperatures, injury-evoked hypersensitivity to cold, and nocifensive responses to cooling compounds. To determine how TRPM8 plays such a critical yet diverse role in cold signaling, we generated mice expressing a genetically encoded axonal tracer in TRPM8 neurons. Based on tracer expression, we show that TRPM8 neurons bear the neurochemical hallmarks of both C-and A␦-fibers, and presumptive nociceptors and non-nociceptors. More strikingly, TRPM8 axons diffusely innervate the skin and oral cavity, terminating in peripheral zones that contain nerve endings mediating distinct perceptions of innocuous cool, noxious cold, and first-and second-cold pain. These results further demonstrate that the peripheral neural circuitry of cold sensing is cellularly and anatomically complex, yet suggests that cold fibers, caused by the diverse neuronal context of TRPM8 expression, use a single molecular sensor to convey a wide range of cold sensations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Takashima¹,

Daniels²,

Knowlton³

et al. 2007

J. Neurosci.

195

214

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“…One equivalent of 3-(2-bromoethyl)indole (1) or intermediate 2 or 3 was dissolved in THF and 1.5 eq of the proper amine, 1.5 eq of TEA, 1.5 eq of NaI and 0.3 eq of (CH 3 COO) 2 Pd were added to this solution (Scheme I). The reaction was conducted under W, at 100°C, for 20 minutes.…”

Section: General Procedures For the Synthesis Of Derivatives 4-12mentioning

confidence: 99%

“…One of the most investigated effects produced by TRPM8 modulation is the analgesia against chronic and neuropathic pain: in fact, it has been reported that peripheral and central activation of TRPM8 induces analgesia, specifically reversing the sensitization of the behavioral reflexes elicited by peripheral nerve injury. 2 Notably, both TRPM8 agonists and antagonists exert analgesic effects: in particular, while TRPM8 agonists produce profound analgesia 2 at very low concentrations, even greater effects have been reported for TRPM8 antagonists. 3 This analgesia modulation represents a novel approach in a largely unmet therapeutic need.…”

Section: Introductionmentioning

confidence: 99%

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

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Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach mainly for the treatment of pain. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. As a result of a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, compound 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, compound 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 = 367±24 nM). Molecular modelling studies using a homology model of a single TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing two different binding modes for the agonist and the antagonist.

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“…It is well known that menthol induces cold and pain sensations in subjects [5]. Application of a given dose of menthol or icilin is associated with cooling perception or pain relief, whereas treatment with higher doses of menthol causes burning, *Address correspondence to this author at the Chemistry and BioScience of Science Course, Graduate School of Science & Engineering, Kagoshima University, Kagoshima, Japan; Tel: 81-99-285-8939; Fax: 81-99-285-8939; Email: kasai@sci.kagoshima-u.ac.jp irritation, and pain [5][6][7][8]. In mammals, cold perception is generally believed to be mediated by a small subpopulation of unmyelinated C and thinly myelinated A primary afferent fibers that discharge in the innocuous temperature range of 15°C -28°C.…”

Section: Introductionmentioning

confidence: 99%

Menthol Induces Surgical Anesthesia and Rapid Movement in Fishes

Kasai¹,

Hososhima²,

Yun-Fei³

2014

TONEURJ

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Abstract:To determine whether fishes respond to menthol, Japanese medaka Oryzias latipes, goldfish Carassius auratus, and zebrafish Danio rerio were exposed to various types of menthol receptors agonists and the behavioral responses to these drugs were observed. Waterbone application of dl-menthol (0.5 mM) induced surgical anesthesia in 100% of medaka, 90% of goldfish, and 100% of zebrafish. The percentage of response increased dose-dependently from 0.2 mM to 0.5 mM. There were no differences in either percentage or latency of the response in surgical anesthesia among dl-, d-, and l-types of menthol. A high (3.0 mM) concentration of any of the three types of menthol induced rapid movement followed by the anesthetic response. Rapid movement was observed with allyl isothiocyanate, a cold nociceptor agonist, but not with icilin, a cold receptor agonist, in medaka and goldfish. Both allyl isothiocyanate and icilin failed to induce surgical anesthesia. To determine the involvement of -aminobutyric acid (GABA) system in menthol-induced surgical anesthesia, the effect of the receptors antagonist for the GABA A was tested. Pretreatment with a specific GABA A receptor antagonist prolonged the latency of the anesthetic response to menthol, but not to cold-water stimulation, in medaka and goldfish. These results demonstrate that menthol can play a role in the induction of surgical anesthesia in fishes, related at least in part to the activation of GABA A receptors, and of rapid movement possibly via cold nociceptors.

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Analgesia Mediated by the TRPM8 Cold Receptor in Chronic Neuropathic Pain

Abstract: TRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states.

Cited by 380 publications

References 61 publications

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Diversity in the Neural Circuitry of Cold Sensing Revealed by Genetic Axonal Labeling of Transient Receptor Potential Melastatin 8 Neurons

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Menthol Induces Surgical Anesthesia and Rapid Movement in Fishes

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