title: Activation of transient receptor potential ankyrin 1 evokes nociception through substance P release from primary sensory neurons.
abstract: To examine mechanisms underlying substance P (SP) release from primary sensory neurons in response to activation of the non-selective cation channel transient receptor potential ankyrin 1 (TRPA1), SP release from cultured rat dorsal root ganglion neurons was measured, using radioimmunoassay, by stimulating TRPA1 with allyl isothiocyanate (AITC), a TRPA1 agonist. AITC-evoked SP release occurred in a concentration- and time-dependent manner. Interestingly, p38 mitogen-activated protein kinase (p38) inhibitor SB203580 significantly attenuated AITC-evoked SP release. The in vivo effect of AITC-evoked SP release from primary sensory neurons in mice was evaluated. Hind paw intraplantar injection of AITC induced nociceptive behaviors and inflammation (edema, thermal hyperalgesia). AITC-induced thermal hyperalgesia and edema were inhibited by intraplantar pre-treatment with either SB203580 or neurokinin-1 receptor antagonist CP96345. Moreover, intrathecal pre-treatment with either CP96345 or SB203580 inhibited AITC-induced nociceptive behaviors and thermal hyperalgesia. Immunohistochemical studies demonstrated that intraplantar AITC injection induced the phosphorylation of p38 in mouse dorsal root ganglion neurons containing SP. These findings suggest that activation of TRPA1 evokes SP release from the primary sensory neurons through phosphorylation of p38, subsequent nociceptive behaviors and inflammatory responses. Furthermore, the data also indicate that blocking the effects of TRPA1 activation at the periphery leads to significant antinociception.
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yoki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Une
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyano
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D007249:Inflammation / Q000139:chemically induced; D017879:Isothiocyanates / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D059225:Nociception / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D011687:Purines; D018040:Receptors, Neurokinin-1; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D013373:Substance P; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D048051:p38 Mitogen-Activated Protein Kinases