Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / drug effects
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Bradykinin / adverse effects
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CHO Cells
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Calcium Signaling / drug effects
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Cricetinae
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Cricetulus
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Interactions
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Humans
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Hyperalgesia / genetics
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Hyperalgesia / metabolism*
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Hyperalgesia / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oocytes
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Pain Measurement / methods
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Rats
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Rats, Sprague-Dawley
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TRPA1 Cation Channel
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Transfection / methods
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Transient Receptor Potential Channels / antagonists & inhibitors
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Transient Receptor Potential Channels / deficiency
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Transient Receptor Potential Channels / genetics
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Transient Receptor Potential Channels / physiology*
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Xenopus
Substances
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TRPA1 Cation Channel
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Transient Receptor Potential Channels
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Trpa1 protein, mouse
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Bradykinin