Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats

Ryan Patel*, Leonor Gonçalves, Robert Newman, Feng Li Jiang, Anne Goldby, Jennifer Reeve, Alan Hendrick, Martin Teall, Duncan Hannah, Sarah Almond, Nicola Brice, Anthony H. Dickenson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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 nerveligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca2+ currents in HEK293 cells stably expressing human TRPM8 with an IC50 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.

Original languageEnglish
Pages (from-to)47-55
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume349
Issue number4
DOIs
Publication statusPublished - Apr 2014

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