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Targeting TRP channels for pain relief.
Eur J Pharmacol. 2013 Sep 15; 716(1-3):61-76.EJ

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 temperature-sensitive Transient Receptor Potential (TRP) channels (so-called "thermoTRPs") on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. In the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels. TRPV1 desensitization by topical agonists (e.g. high concentration capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific 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 past few years a number of potent, small molecule TRPV1, TRPV3 and TRPA1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. TRPM8 antagonists are following closely behind for cold allodynia. Early TRPV1 antagonists in the clinic, however, showed worrisome adverse effects including hyperthermia and impaired noxious heat sensation. These adverse effects placed the patients at risk for scalding injury and prompted their withdrawal from the clinical trials. Second generation TRPV1 antagonists that do not cause core body temperature elevation have been reported, although the therapeutic utility of this class of compounds is not yet known. This review discusses the promise and challenges of developing TRP channel antagonists as a new generation of pain therapeutics.

Authors+Show Affiliations

Neuroscience Discovery Research and Pain Discovery Research, AbbVie Inc, North Chicago, IL 60064, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

23500195

Citation

Brederson, Jill-Desiree, et al. "Targeting TRP Channels for Pain Relief." European Journal of Pharmacology, vol. 716, no. 1-3, 2013, pp. 61-76.
Brederson JD, Kym PR, Szallasi A. Targeting TRP channels for pain relief. Eur J Pharmacol. 2013;716(1-3):61-76.
Brederson, J. D., Kym, P. R., & Szallasi, A. (2013). Targeting TRP channels for pain relief. European Journal of Pharmacology, 716(1-3), 61-76. https://doi.org/10.1016/j.ejphar.2013.03.003
Brederson JD, Kym PR, Szallasi A. Targeting TRP Channels for Pain Relief. Eur J Pharmacol. 2013 Sep 15;716(1-3):61-76. PubMed PMID: 23500195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting TRP channels for pain relief. AU - Brederson,Jill-Desiree, AU - Kym,Philip R, AU - Szallasi,Arpad, Y1 - 2013/03/14/ PY - 2012/09/20/received PY - 2013/03/04/accepted PY - 2013/3/19/entrez PY - 2013/3/19/pubmed PY - 2014/4/25/medline KW - Capsaicin KW - Resiniferatoxin KW - TRPA1 KW - TRPM8 KW - TRPV1 KW - TRPV3 KW - ThermoTRP channels SP - 61 EP - 76 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 716 IS - 1-3 N2 - Preclinical research has recently uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent opportunities for pharmacological intervention. Manipulating temperature-sensitive Transient Receptor Potential (TRP) channels (so-called "thermoTRPs") on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. In the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels. TRPV1 desensitization by topical agonists (e.g. high concentration capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific 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 past few years a number of potent, small molecule TRPV1, TRPV3 and TRPA1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. TRPM8 antagonists are following closely behind for cold allodynia. Early TRPV1 antagonists in the clinic, however, showed worrisome adverse effects including hyperthermia and impaired noxious heat sensation. These adverse effects placed the patients at risk for scalding injury and prompted their withdrawal from the clinical trials. Second generation TRPV1 antagonists that do not cause core body temperature elevation have been reported, although the therapeutic utility of this class of compounds is not yet known. This review discusses the promise and challenges of developing TRP channel antagonists as a new generation of pain therapeutics. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/23500195/Targeting_TRP_channels_for_pain_relief_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(13)00173-8 DB - PRIME DP - Unbound Medicine ER -