Recent research into the neurological pathways of temperature sensation portends relief for those suffering from chronic pain. The new study, published in the 22 August issue of Current Biology, investigates the mechanism by which menthol and icilin, two compounds known to create 'sensations of coldness' in rats and humans, induce analgesia in rats.

The analgesic effects of cold and menthol have been recognized for many centuries, but the neurological mechanism that mediates that effect has been unknown. Researchers at the University of Edinburgh (Scotland) set out to test whether TRPM8, a 'cool-sensitive' transient receptor potential cation channel, is involved in the pain-relief mediation of molecules that create coldness sensations, such as menthol and icilin. As an experimental model, Susan Fleetwood-Walker, Rory Mitchell, and their colleagues chose adult male Wistar rats with chronic constriction injury to sciatic nerve; these animals are reflexively sensitive to certain stimuli, the degree of which can be measured by their behavior.

To test TRPM8's involvement in the analgesic effects of cold-mimicking molecules, Fleetwood-Walker and Mitchell applied solutions of menthol or icilin (either topically on the affected paw or intrathecally) to the rats and measured their sensitization to thermal and mechanical stimuli as compared to untreated controls. Low concentrations of both solutions of menthol and icilin significantly reversed the sensitization of the rats, though icilin had a more marked effect. In a subsequent experiment, the researchers 'knocked down' TRPM8 levels in some of the rats using antisense oligonucleotides; they then repeated their original experiment on these 'knockdown' rodents in order to determine whether the sensitization reversal involved TRPM8. They discovered that the knockdown nullified the reversal effects of icilin, thereby incriminating TRPM8 as a vital player in cold-induced analgesia.

Fleetwood-Walker and Mitchell hope these positive results will soon translate into chronic pain treatment for humans, especially a treatment for neuropathic pain. “Neuropathic pain is inadequately treated using current analgesic drugs,” the authors tell Lab Animal, “Clinically, we expect that effective pain relief, with little or no side effects, will be achieved by topical application of TRPM8 activators in a cream or similar vehicle.” But the work is far from finished: “Much more needs to be done,” the authors conclude, “to fully clarify the molecular mechanisms involved and thereby potentially generate further new targets for therapeutic intervention.”