title: TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid             Δ(9)-tetrahydrocannabiorcol.
abstract: TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for                 analgesics. Here we show that the antinociceptive effects of spinal and systemic                 administration of acetaminophen                     (paracetamol) are lost in                     Trpa1(-/-) mice. The                 electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and                 human TRPA1. These metabolites also activate native TRPA1 and, as a consequence,                 reduce voltage-gated calcium and sodium currents in primary sensory neurons. The                     N-acetyl-p-benzoquinoneimine metabolite                     L-cysteinyl-S-acetaminophen was detected in the                 mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal                 administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic                 TRPA1 activator cinnamaldehyde                 produced antinociception that was lost in                         Trpa1(-/-) mice.                 Intrathecal injection of a non-electrophilic cannabinoid,                     Δ(9)-tetrahydrocannabiorcol, also produced                 TRPA1-dependent antinociception in this test. Our study provides a molecular                 mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a                 potential pharmacological strategy to alleviate pain.
authors: King's College London, Wolfson Centre for Age-Related Diseases,                     London                 SE1 1UL, UK.
authors: David A
authors: DA
authors: Andersson
authors: Clive
authors: C
authors: Gentry
authors: Lisa
authors: L
authors: Alenmyr
authors: Dan
authors: D
authors: Killander
authors: Simon E
authors: SE
authors: Lewis
authors: Anders
authors: A
authors: Andersson
authors: Bernard
authors: B
authors: Bucher
authors: Jean-Luc
authors: JL
authors: Galzi
authors: Olov
authors: O
authors: Sterner
authors: Stuart
authors: S
authors: Bevan
authors: Edward D
authors: ED
authors: Högestätt
authors: Peter M
authors: PM
authors: Zygmunt
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007097:Imines / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000700:Analgesics; D016227:Benzoquinones; D002186:Cannabinoids; D007097:Imines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000082:Acetaminophen; C004532:quinone; D000171:Acrolein; C028473:N-acetyl-4-benzoquinoneimine; C012843:cinnamaldehyde; D002118:Calcium