TRPV1 Antagonists as Analgesic Agents

The last decade (2001 - 2010), declared as the Decade of Pain Control and Research by the United States Con- gress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into ad- ditional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing impor- tant side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effec- tive management of chronic pain needs a multidisciplinary management approach and still represents one of the most ur- gent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the genera- tion and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This re- view focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular 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. De- sensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antago- nists have been advanced into clinical 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 humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this impor- tant side effect.