oa Editorial [Hot Topic: New Developments in the Medicinal Chemistry of Vanilloid TRPV1 and Related Receptors (Guest Editor: Arpad Szallasi)]

With 462 reviews over the past decade, Transient Receptor Potential (TRP) channels arguably represent one of today's most extensively reviewed pharmacological targets. The vanilloid (capsaicin) receptor TRPV1 itself has been subject to 271 reviews and was featured in several books since its molecular cloning in 1997. One may ask, somewhat sceptically, why to add another review to this pile? My answer is two-fold. First, our knowledge on TRP channels is rapidly evolving and thus the literature needs constant critical re-evaluation. Second, this special issue is unique in that it attempts to form a coherent picture of the field from the gating physiology of TRP channels through disease-related changes in TRP channels expression to preclinical and clinical studies with compounds targeting TRPV1 for pain relief to emerging therapeutic targets (e.g. TRPA1, TRPV3 and TRPM8) that are co-expressed with TRPV1 on nociceptive neurons. Despite recent advances in our understanding of the mechanisms that cause and maintain pain, chronic pain still represents a major treatment challenge to healthcare providers. The American Pain Society estimates that at least 50 million Americans are affected by chronic pain, rendering many patients partially or totally disabled. Chronic pain already costs the country billions of dollars in health care expenses and lost productivity and the situation will certainly worsen as the population continues to age. Unfortunately, most analgesic drugs on the market today either provide unsatisfactory pain relief or their use is saddled by dangerous side-effects. Clearly, there is a great need for novel, potent analgesic drugs with improved safety and tolerability. The discovery of temperature-sensitive TRP channels (so-called “thermoTRP”s) in nociceptive neurons has spawned extensive research efforts to understand the role of these channels in the initiation and maintenance of pain conditions and to identify potent and selective small molecule antagonists that can be exploited for therapeutic purposes. Since these channels are strategically located at the periphery where the pain pathway begins, it is hoped that TRP antagonists will be devoid of the sideeffects that plague the clinical use of centrally-acting analgesic agents. Of note, the expression of thermoTRP channels is not restricted to nociceptive neurons. Indeed, there is good evidence that the therapeutic potential of thermoTRP blockers extend beyond pain and include airway disorders (e.g. chronic cough, asthma and chronic obstructive pulmonary disease), overactive bladder, skin diseases (e.g. skin-derived pruritus, acne and alopecia or hirsutism), and cancer, just to name a few examples. Of TRP channels that are present in nociceptive neurons, the vanilloid (capsaicin) receptor TRPV1 has attracted the most attention so far partly due to the well-documented clinical potential of capsaicin to relieve pain. This explains the focus of this special issue on TRPV1. Desensitization to capsaicin is a unique approach to lasting pain relief. After an initial excitatory response (that can be minimized by topical analgesic agents like lidocaine), TRPV1-expressing neurons develop a long-lasting (weeks in animal experiments and several months in clinical studies) refractory state in which the neurons are silent regardless of the nature of the noxious stimulus. This is important since capsaicin-sensitive neurons express a broad range of channels that are involved in pain perception. Importantly, all of these channels are silent during capsaicin desensitization....