TRPV1 activators ("vanilloids") as neurotoxins

A distinct subset of primary sensory neurons is distinguished by their unique sensitivity to capsaicin, the pungent ingredient in hot chili peppers. The initial excitation by capsaicin of these neurons is followed by a long-lasting, but fully reversible, refractory state (traditionally termed as desensitization) or under certain conditions, like neonatal treatment, frank neurotoxicity. This neurotoxic action was extensively used to identify capsaicin-sensitive neuronal pathways and to explore their physiological function. In 1997, a specific receptor for capsaicin and related compounds (collectively referred to as vanilloids) was identified as transient receptor potential cation channel subfamily V member 1 (TRPV1), a multifunctional channel involved in thermosensation (heat) and taste perception (e.g., peppers and vinegar). Importantly, TRPV1 also functions as a molecular integrator for a broad range of seemingly unrelated noxious stimuli including venoms from spiders and jellyfish. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Ablation of sensory neurons by vanilloids is, however, not only a research tool but also has a clear therapeutic potential. Currently, site- specific resiniferatoxin (an ultrapotent capsaicin analog) injections are being evaluated as "molecular scalpels" to achieve permanent analgesia in cancer patients with chronic, intractable pain. In this chapter, we review our knowledge of the molecular mechanisms underlying vanilloid-induced neurotoxicity, which includes both TRPV1-mediated and independent signalling pathways.