A review.Chronic neuropathic pain is notoriously difficult to treat.Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief.The need for better drugs is universally recognized.However, despite a substantial investment of resources by the pharmaceutical industry to identify alternative treatments, the effective management of chronic pain remains an unmet medical need.Recently, preclin. research has uncovered new mol. mechanisms underlying the generation and transduction of pain, many of which represent new targets for pharmacol. intervention.This review focuses on transient receptor potential (TRP) channel vanilloid 1 (TRPV1) as a target for treating chronic pain.TRPV1 is a multifunctional channel involved in thermosensation (heat) and taste perception (e.g. peppers and vinegar).Importantly, TRPV1 also functions as a mol. integrator for a broad variety of seemingly unrelated noxious stimuli.Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury.Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clin. use for decades to treat chronic painful conditions like diabetic neuropathy.Currently, site-specific capsaicin and resiniferatoxin (an ultrapotent capsaicin analog) injections are being evaluated as "mol. scalpels" to achieve permanent analgesia.Most recently, a number of potent, small mol. TRPV1 antagonists have been advanced into clin. trials for pain relief.Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in men, leading to their withdrawal from the clin. trials.Clearly, the balance between the beneficial actions of drugs targeting TRPV1 and the adverse effects must be carefully and pragmatically evaluated to determine if these drugs could emerge as the next generation of pain killers.
