Correspondence to David P. Corey: dcorey@ hms. harvard. edu Abbreviations used in this paper: DRG, dorsal root ganglion; TRP, transient receptor potential. source of the stimuli; in some cases such as noxious cold temperatures, the stimulus evokes several distinct sensations. For instance, the perception of pain may be combined with the perception of cold in the general sensation of noxious cold. To understand such a complex process, many have focused on identifying the molecular thermosensors residing at the nerve terminals using chemical mimetics of hot or cold temperatures. This approach is exemplified by the use of capsaicin, the stimulant found in hot chili peppers, to identify its receptor TRPV1. Studies on TRPV1 have provided a productive entryway to understanding the molecular basis of thermosensation, leading by both analogy and homology to the putative cold sensors TRPM8 and TRPA1.

Complexities of Cold Sensation Found in species ranging from yeast to human, transient receptor potential (TRP) channels typically contain six transmembrane domains that form a central pore, as well as differing amino and carboxyl domains that impart differential sensitivity to various sensory stimuli (Wang and Woolf, 2005). After the finding that TRPV1 is involved in noxious heat sensation, investigators found other TRP channels that are activated by temperatures ranging from noxious hot to cool (Patapoutian et al., 2003; Tominaga and Caterina, 2004). TRPM8, for instance, is activated at temperatures below 23 C and chemicals that produce a cool sensation, such as menthol and icilin (McKemy et al., 2002; Peier et al., 2002). The sensation of painful cold is distinct from the sensation of cool because it encompasses an additional percept of pain. Painful cold sensations are elicited by temperatures of 15 C and below. TRPA1 (originally known as ANKTM1; Jaquemar et al., 1999) was reported to be activated by temperatures below 16 C and was proposed as a sensor for painful or noxious cold (Story et al., 2003). TRPA1 shares some pharmacology with TRPM8. Both are activated by icilin and menthol, although menthol blocks TRPA1 at higher concentrations (Karashima et al., 2007). Other studies found instead that cold did not activate TRPA1 (Jordt et al., 2004), or that the effect was an indirect activation of TRPA1 through cold-induced