A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition.
Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.
Petrus
Matt
M
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA. mpetrus@gnf.org
Peier
Andrea M
AM
Bandell
Michael
M
Hwang
Sun Wook
SW
Huynh
Truc
T
Olney
Nicholas
N
Jegla
Tim
T
Patapoutian
Ardem
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001920:Bradykinin / Q000009:adverse effects; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D014162:Transfection / Q000379:methods; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014981:Xenopus
D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D001920:Bradykinin