Pharmacological studies on icilin in rats

Icilin, the cold-inducing agent, was first classified as a "quasi-morphine withdrawal inducing compound." Acute administration of icilin into drug-naive animals elicits behaviors observed in animals undergoing opioid withdrawal or abstinence. Intraperitoneal icilin produces a syndrome comprised of excessive grooming, abdominal writhing, and vigorous wet-dog shakes (WDS)-in rats. Although current interest in icilin lies in its cold-inducing properties, we wished to investigate the behavioral pharmacology of the compound in rats to confirm a central component of its mechanism.;We show that icilin elicits WDS when administered intraperitoneally or orally, yet does not produce WDS when given intracerebroventricularly, intrastriatally or intrathecally. This suggests that icilin acts in the periphery to elicit its behavior. Nevertheless, non-restricted mu (morphine and buprenorphine) and kappa (nalfarafine and U50,488H) receptor agonists inhibit icilin-induced WDS, while ICI 204,448, the peripherally restricted kappa agonist, does not. We conclude that icilin-induced shaking resembles that of opioid withdrawal through an interaction with the central nervous system.;Submaximal doses of icilin (0.50, 0.75 mg/kg, i.p.) produces dose- and time-related glutamate release in the dorsal striatum, a brain region implicated in movement, 30 min following administration. At 0.25 mg/kg, icilin elicits few WDS and does not increase glutamate levels. These findings parallel that which was observed behaviorally following icilin administration.;Inhibition of icilin-evoked glutamate release in the dorsal striatum with nalfurafine suggests that there is an intrastriatal component to icilin-induced WDS. Likewise, intrastriatal infusion of norbinaltorphimine, the kappa receptor antagonist, reverses nalfurafine inhibition of icilin-induced WDS and glutamate release, confirming this component. Nevertheless, nalfurafine does not completely antagonize icilin-induced WDS, suggesting that residual shaking occurs via an extrastriatal component. Although icilin does not bind to opioid or orphanin receptors directly and does not affect opioid or orphanin stimulation of [ 35S]GTPgammaS in the striatum, this work proposes a central component, while showing the neurochemical effect that icilin exerts on the central nervous system of rats downstream of activation of TRPA1 and TRPM8 in the periphery. By doing so, we extend the in vivo profile of icilin, a key compound in the study of cold transduction, quasi-morphine withdrawal and overt stimulant behavior.