Nociceptive sensory peripheral neurons often express both heat sensitive (VR1) and cold-sensitive (CMR1 (rat); TRPM8 (human)) receptors that are part of the transient receptor potential (TRP) superfamily. Icilin (AG 3-5) is a synthetic CMR1/TRPM8 super agonist that is 2.5-fold more efficacious and nearly 200-fold more potent than the reference cold thermosensory agonist, l-menthol. Icilin induces sensations of intense cold when applied orally in humans, and induces 'wet dog shakes', a behavioral marker of cold sensation, when given to rats. Icilin should serve as the reference cold nociceptive agonist for TRP-type ion channels in the future.
