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Advances in Health and Disease. Volume 5
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01.Targeting TRPV1 for Pain Relief: Should we Quench or Reignite the Fire?
02.Spinal Cord Neural Plasticity in Chronic Pain and its Clinical Implication
03.Plasticity in Chronic Pain Syndromes: The Role of Neuroimaging
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Targeting TRPV1 for Pain Relief: Should we Quench or Reignite the Fire? $45.00
Authors:  Marcello Trevisani and Arpad Szallasi
Abstract:
Preclinical research has recently uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent opportunities for pharmacological intervention. Manipulating TRP (Transient Receptor Potential) channels on nociceptive neurons is a particularly attractive strategy in drug development in that it targets the beginning of the pain pathway. The vanilloid (capsaicin) receptor TRPV1 is a multifunctional channel involved in thermosensation (heat) and taste perception (e.g. peppers and vinegar). Importantly, TRPV1 also functions as a molecular integrator for a broad range 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 clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific capsaicin and resiniferatoxin (an ultrapotent capsaicin analogue) injections are being evaluated as “molecular scalpels” to achieve permanent analgesia in cancer patients with chronic, intractable pain. In the last five years, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. Some of these compounds have successfully passed Phase 1 safety and tolerability studies in healthy volunteers into Phase 2 studies to access efficacy in patients, whereas others showed worrisome unforeseen adverse effects (most important, hyperthermia and impaired noxious heat sensation placing the patient at risk for scalding injury) in men, prompting their withdrawal from the clinical trials. In this paper, we first give an overview of the clinical trials with TRPV1 agonists (that “reignite the fire”) and then summarize the current state of the field pertaining to the known TRPV1 antagonists (“quenching the fire”) in clinical development. 


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Targeting TRPV1 for Pain Relief: Should we Quench or Reignite the Fire?