title: Spinal transient receptor potential ankyrin 1 channel induces mechanical hypersensitivity, increases cutaneous blood flow, and mediates the pronociceptive action of dynorphin A.
abstract: We characterized pain behavior and cutaneous blood flow response induced by activation of the spinal transient receptor potential ankyrin 1 (TRPA1) channel using intrathecal drug administrations in the rat. Additionally, we assessed whether the pronociceptive actions induced by intrathecally administered dynorphin A, cholecystokinin or prostaglandin F(2α) are mediated by the spinal TRPA1 channel. Cinnamaldehyde, a TRPA1 agonist, produced a dose-related (3-10 μg) cutaneous blood flow increase and mechanical hypersensitivity effect. These effects at the currently used doses were of short duration and attenuated, although not completely, by pretreatment with A-967079, a TRPA1 antagonist. The cinnamaldehyde-induced hypersensitivity was also reduced by pretreatment with minocycline (an inhibitor of microglial activation), but not by carbenoxolone (a gap junction decoupler). In vitro study, however, indicated that minocycline only poorly blocks the TRPA1 channel. The mechanical hypersensitivity effect induced by dynorphin A, but not that by cholecystokinin or prostaglandin F(2α), was attenuated by a TRPA1 antagonist Chembridge-5861528 as well as A-967079. The cinnamaldehyde-induced cutaneous blood flow increase was not suppressed by MK-801, an NMDA receptor antagonist, or bicuculline, a GABA(A) receptor antagonist. The results indicate that spinal TRPA1 channels promote mechanical pain hypersensitivity and due to antidromic activation of nociceptive nerve fibers increase cutaneous blood flow. The attenuation of the cinnamaldehyde-induced hypersensitivity effect by minocycline may be explained by action other than block of the TRPA1 channel. Moreover, the spinal TRPA1 channel is involved in mediating the pronociceptive action of dynorphin A, but not that of the spinal cholecystokinin or prostaglandin F(2α).
authors: Institute of Biomedicine/Physiology, POB 63, University of Helsinki, 00014 Helsinki, Finland.
authors: H
authors: H
authors: Wei
authors: M
authors: M
authors: Saarnilehto
authors: L
authors: L
authors: Falck
authors: H
authors: H
authors: Viisanen
authors: M
authors: M
authors: Lasierra
authors: A
authors: A
authors: Koivisto
authors: A
authors: A
authors: Pertovaara
mesh_terms: D000171:Acrolein / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001416:Back Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D002766:Cholecystokinin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism; D015237:Dinoprost / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D008911:Minocycline / Q000008:administration & dosage / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage / Q000627:therapeutic use; D010812:Physical Stimulation / Q000009:adverse effects; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C560402:A 967079; D018712:Analgesics, Non-Narcotic; D009419:Nerve Tissue Proteins; D010091:Oximes; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D004399:Dynorphins; D000171:Acrolein; D002766:Cholecystokinin; D015237:Dinoprost; D008911:Minocycline; C012843:cinnamaldehyde