A New Class of Analgesics Exerts a Dual Modulation on TRPA1 and TRPV1 Channels

Abstract

The Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) ion channels belong to the TRP superfamily and are both integrators of a variety of noxious stimuli.Both channels are non selective cation channels which exert pleiotropic functions in a variety of cells; more specifically they colocalize in primary sensory neurons of the trigeminal, vagal and dorsal root ganglia (DRG).TRPA1 is activated by a number of pungent and irritant reactive chemical compounds including allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon oil), allicin (onions), carvacrol (oregano), polygodial (Tasmanian pepper) and formaldehyde (formalin); all of these molecules elicit a painful burning and a prickling sensation.TRPV1 is activated by noxious stimuli including high temperature, pH, and vanilloid compounds such as capsaicin. Moreover increased expression of TRPV1 was detected in prostate, colon, and pancreatic cancers, revealing a relevant role of TRPV1 as tumor suppressor.In this context, we describe a new class of water soluble derivatives of lipoic acid [1], which proved to block TRPA1 channels.We screened a small molecule compounds library, by patch- clamp recordings on culture cells expressing both the human and the mouse isoforms of TRPA1 channel, to compare the potency of each molecule towards well-known TRPA1 agonists (AITC, Menthol, cinnamaldehyde, oxaliplatin); selectivity studies showed no appreciable block by these molecules of TRPM8, hERG and NaV channels.Finally we showed that a subgroup of these compounds is able to activate TRPV1 channels, suggesting interesting applications of our molecules for the treatment of many diseases.[1] Nativi C., Gualdani R. et al. (2013) ‘A TRPA1 antagonist reverts oxaliplatin-induced hyperalgesia’. Scientific Reports, 3, 1-10.This work was supported by Ente Cassa di Risparmio di Firenze.