Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats.
Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.).
Ryan
R
Patel
Leonor
L
Gonçalves
Robert
R
Newman
Feng Li
FL
Jiang
Anne
A
Goldby
Jennifer
J
Reeve
Alan
A
Hendrick
Martin
M
Teall
Duncan
D
Hannah
Sarah
S
Almond
Nicola
N
Brice
Anthony H
AH
Dickenson
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D056587:Cryopyrin-Associated Periodic Syndromes / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D059348:Peripheral Nerve Injuries / Q000150:complications* / Q000378:metabolism / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
C588262:6-((2-(2-fluoro-6-(trifluoromethyl)phenoxy)-2-methylpropyl)carbamoyl)pyridine-3-carboxylic acid; D009539:Nicotinic Acids; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat; D002118:Calcium