Molecular Mechanisms of TRPV1-Mediated Thermal Hypersensitivity

摘要

Pain occurs when noxious thermal, mechanical, or chemical stimuli excite the peripheral terminals of specialized primary afferent neurons called nociceptors (Wood and Perl 1999; Woolf and Salter 2000; Scholz and Woolf 2002). Many kinds of ionotropic and metabotropic receptors are involved in this process (Cesare and McNaughton 1997; Caterina and Julius 1999; McCleskey and Gold 1999; Julius and Basbaum 2001). Capsaicin (vanilloid) receptors are nociceptor-specific channels that serve as the molecular target of capsaicin, the pungent ingredient in hot chili peppers (Szallasi and Blumberg 1999). Caterina and colleagues used an expression-cloning method to isolate a gene encoding a capsaicin receptor. They found that the receptor protein was an ion channel with six transmembrane domains having high Ca~(2+) permeability (Caterina et al. 1997) (Fig. 1). When expressed in heter-ologous systems, the cloned capsaicin receptor (TRPV1) can also be activated by noxious heat (with a thermal threshold >43degC) or by protons (acidification), both of which cause pain in vivo (Caterina et al. 1997; Tominaga et al. 1998; Tominaga 2000; Caterina and Julius 2001). Furthermore, analyses of mice lacking TRPV1 have shown that TRPV1 is essential for selective modalities of pain sensation and for thermal hyperalgesia induced by tissue injury (Caterina et al. 2000; Davis et al. 2000).