Title: Transient receptor potential channels as novel drug targets
Abstract: At least 6 members of the family of the transient receptor potential (TRP) channels are expressed in defined subpopulations of primary sensory neurons (nociceptors), where they mediate acute nociceptive responses and contribute to allodynic and hyperalgesic conditions. Most prominent channels are the vanilloid 1 (TRPV1), which is activated by capsaicin, protons, and certain eicosanoids, and the ankyrin 1 (TRPA1). TRPA1 is uniquely gated by an unprecedented series of reactive exogenous (mustard oil, cinnamaldehyde and others) and endogenous molecules. These latter molecules include byproducts of oxidative stress, as hydrogen peroxide, 4-hydroxynonenal, oxononenal, and many others electrophilic agonists, which, by binding to key cysteine residues, cause channel activation and nociceptor stimulation. All TRPA1-expressing neurons and the majority of TRPV1-expressing neurons express and release sensory neuropeptides, which mediate neurogenic inflammatory responses. Calcitonin gene–related peptide (CGRP) released from perivascular trigeminal nerve endings upon TRPV1 or TRPA1 stimulation has been now recognized as a major contributing factor of migraine headaches. A series of agents, known to trigger migraine attacks, have been identified as selective stimulants of TRPV1 or TRPA1, thereby producing CGRP-dependent meningeal vasodilatation. There is growing evidence that TRPV1 and, even at a larger extent, TRPA1 contribute to thermal and mechanical hypersensitivity in models of inflammatory and neuropathic pain. In particular, recent findings underscore the critical role of TRPA1 in models of chemotherapeutic-induced peripheral neuropathy. The desensitizing action on nociceptor function of topical and repeated application of the TRPV1 agonist, capsaicin, has been used for a long time for the treatment of pain in postherpetic neuralgia and in diabetic neuropathy. In contrast, clinical development of TRPV1 antagonists has been hampered by unexpected evidence obtained in Phase I studies of their ability to increase body temperature and heat pain threshold. The underlying hypothesis that TRPA1 plays a major role in pain associated with increases in oxidative stress is boosting major efforts in the discovery and development of TRPA1 antagonists.