Management of chronic and pathological pain without incurring systemic side effects is a major medical challenge.Currently available drugs, such as non-steroidal anti-inflammatory drugs or opioid agonists, are efficacious through peripheral and central mechanisms. However, various complications and development of tolerance are serious problems. Other classes of drugs, such as anti-depressants and anti-convulsants, are often used for multiple pain syndromes. However, the efficacy of these drugs is commonly unsatisfactory, and their mechanism of action is not clear. For establishing novel, selective anti-hyperalgesic therapeutic approaches, targeted inhibition of pain-specific pathways or molecules would be ideal, and these approaches suggest straightforward strategies. A new era of exploring such “straightforward” approaches was opened with regard to peripheral nociceptors by the identification of the vanilloid receptor-1 (VR-1), which was designated transient receptor potential channel vanilloid subtype 1 (TRPV1). TRPV1 is a receptor for capsaicin, proton, and noxious heat. Capsaicin has long been known to be a natural compound capable of evoking an intense burning sensation and pain in human and experimental animals. It has been hypothesized that specific manipulation of TRPV1 may selectively relieve pain under injury or inflammatory conditions. Interfering with TRPV1 has been a central focus of these efforts during the 15 years following the cloning of TRPV1. Numerous pharmacological compounds have been developed targeting TRPV1. The characteristics and roles of TRPV1 have been rigorously studied using multiple approaches ranging from biophysical characterization to clinical trials in human subjects. Meanwhile, other members of the TRP channel family in addition to TRPV1 have been suggested to be also involved in nociception under pathophysiological conditions. These studies have identified targets in addition to TRPV1 as potential candidates for selective anti-hyperalgesic treatment
free from complications.
In this special issue of The Open Pain Journal, current knowledge regarding the roles of various TRP channels in pain is reviewed. Multiple scientists in academia and the pharmaceutical industry took part in this exciting project, and have shared their opinions regarding the prospects for relieving pain through targeting TRP channels.
In the opening chapter, “Changes in TRP channels expression in painful conditions,” Bishnoi and Premkumar summarize the involvement of various members of the TRP channel family in nociception. The five following chapters are devoted to a discussion of the role of various TRP channels in specific pathological conditions. Blackshaw and colleagues review the evidence for the roles of “TRP channels in visceral pain.” They discuss the contribution of TRP channels, especially TRPV1, TRPV4, TRPA1, and TRPM8, to pain signaling in visceral systems in various visceral pathological models. The roles of “TRP channels in dental pain” are reviewed by Chung and Oh. The expression of various TRP channels in pulpal afferents and odontoblasts is summarized, and their potential contribution to dental pain by thermal and mechanical stimuli is discussed. In “The role of TRP channels in migraine,” Oxford and Hurley review the potential roles of TRP channels in a trigeminovascular system, their involvement in migraine attack, and recent clinical trials. Fernandes et al. discuss “TRP receptors in arthritis, gaining knowledge for translation from experimental models”. They review current knowledge pertaining to the therapeutic potential of TRP channels, primarily TRPV1 and TRPA1, for treating pain in osteoarthritis and other arthritic conditions. The roles of “Transient Receptor Potential channels in chemotherapy-induced neuropathy” are discussed by Nassini et al. In this chapter, the current understanding of the involvement of TRPV1, TRPV4, TRPM8, and TRPA1 in chemotherapy-induced neuropathy is highlighted.
The next three chapters analyze the status of therapeutic approaches targeting TRPV1 using specific agonists and antagonists. In effects of topical capsaicin on cutaneous innervation: Implications for pain management Bley reviews the potential mechanisms of topical application of high concentrations of capsaicin to skin, and suggests pharmacokinetic and pharmacodynamic considerations of this therapy. Iadarola and colleagues discuss how site-specific administration of resiniferatoxin, an ultrapotent capsaicin analog, can overcome the limitations of topical capsaicin therapy, and they give an insight into the clinical trials using resiniferatoxin for permanent pain relief in cancer patients with intractable pain. Trevisani and Gatti discuss “TRPV1 antagonists as analgesic agents.” The authors review preclinical and clinical studies addressing the application of small molecule TRPV1 antagonists as anti-hyperalgesic thera-pies, and update current status of clinical trials
TRPV4: A Physio and Pathophysiologically Significant Ion Channel