title: Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat.
abstract: The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent neurons. On the proximal nerve ending within the spinal dorsal horn, TRPA1 regulates transmission to spinal interneurons, and thereby pain hypersensitivity. Here we assessed whether the contribution of the spinal TRPA1 channel to pain hypersensitivity varies with the experimental pain model, properties of test stimulation or the behavioral pain response. The antihypersensitivity effect of intrathecally (i.t.) administered Chembridge-5861528 (CHEM; a selective TRPA1 channel antagonist; 5-10μg) was determined in various experimental models of pain hypersensitivity in the rat. In spinal nerve ligation and rapid eye movement (REM) sleep deprivation models, i.t. CHEM attenuated mechanical hypersensitivity. Capsaicin-induced secondary (central) but not primary (peripheral) mechanical hypersensitivity was also reduced by i.t. administration of CHEM or A-967079, another TRPA1 channel antagonist. Formalin-induced secondary mechanical hypersensitivity, but not spontaneous pain, was suppressed by i.t. CHEM. Moreover, mechanical hypersensitivity induced by cholekystokinin in the rostroventromedial medulla was attenuated by i.t. pretreatment with CHEM. Independent of the model, the antihypersensitivity effect induced by i.t. CHEM was predominant on responses evoked by low-intensity stimuli (⩽6g). CHEM (10μg i.t.) failed to attenuate pain behavior in healthy controls or mechanical hypersensitivities induced by i.t. administrations of a GABA(A) receptor antagonist, or NMDA or 5-HT(3) receptor agonists. Conversely, i.t. administration of a TRPA1 channel agonist, cinnamon aldehyde, induced mechanical hypersensitivity. The results indicate that the spinal TRPA1 channel exerts an important role in secondary (central) pain hypersensitivity to low-intensity mechanical stimulation in various pain hypersensitivity conditions. The spinal TRPA1 channel provides a promising target for the selective attenuation of a central mechanism contributing to pathophysiological pain.
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland Orion Corporation, OrionPharma, R&D, Turku, Finland King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.forename: Ari
authors.initials: A
authors.lastname: Koivisto
authors.forename: Marja
authors.initials: M
authors.lastname: Saarnilehto
authors.forename: Hugh
authors.initials: H
authors.lastname: Chapman
authors.forename: Katja
authors.initials: K
authors.lastname: Kuokkanen
authors.forename: Bin
authors.initials: B
authors.lastname: Hao
authors.forename: Jin-Lu
authors.initials: JL
authors.lastname: Huang
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Antti
authors.initials: A
authors.lastname: Pertovaara
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D017487:Ankyrins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002211:Capsaicin / Q000009:adverse effects; D002766:Cholecystokinin / Q000009:adverse effects; D002935:Cinnamomum zeylanicum / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D016202:N-Methylaspartate / Q000009:adverse effects; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000150:complications; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012892:Sleep Deprivation / Q000150:complications; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels
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; D017487:Ankyrins; D015220:Calcium Channels; D011687:Purines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D005557:Formaldehyde; D016202:N-Methylaspartate; D002766:Cholecystokinin; D002211:Capsaicin