Molecular mechanisms of trigeminal nociception and sensation of pungency.

One characteristic shared by many nociceptive neurons is sensitivity to capsaicin, the main pungent ingredient of ‘hot’ chili peppers (Szallasi and Blumberg, 1999). When a capsaicin receptor was isolated using a Ca2+-imaging-based expression cloning method, it was designated vanilloid receptor subtype 1 (VR1) because a vanilloid moiety constitutes an essential chemical component of capsaicin (Caterina et al., 1997). Capsaicin receptor TRPV1 is a member of the large TRP (transient receptor potential) superfamily of ion channels (Clapham, 2003), whose prototypical member, TRP, was found to be deficient in a Drosophila mutant exhibiting abnormal responsiveness to continuous light (Montell and Rubin, 1989). Patch-clamp recordings from HEK293 cells expressing TRPV1 revealed that capsaicin-activated TRPV1 currents exhibit non-selective cation permeability with outwardly rectifying current-voltage relationship. TRPV1 can be activated by at least three different pain-producing stimuli—capsaicin, heat (>43°C) or protons (acidification)—all of which are known to cause pain in vivo (Caterina et al., 1997; Tominaga et al., 1998). In addition to capsaicin, piperine and gingerone, the main pungent ingredient of black pepper and ginger respectively, were found to activate TRPV1. TRPV1 transcript and protein were found to be most highly expressed in sensory neurons including trigeminal neurons. Moreover, in situ hybridization and immunostaining revealed that, within dorsal root and trigeminal sensory ganglia (DRG and TG, respectively), TRPV1 expression predominated in small diameter cell bodies, most of which give rise to unmyelinated C-fibers. Furthermore, analyses of mice lacking TRPV1 have shown that TRPV1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia (Caterina et al., 2000). Thus, TRPV1 is a central molecule for detecting nociceptive stimuli.