title: Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.
abstract: Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Stanley
authors.initials: S
authors.lastname: DiDomenico
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perner
authors.forename: Joe P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Gricelda H
authors.initials: GH
authors.lastname: Simler
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Steve P
authors.initials: SP
authors.lastname: McGaraughty
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003080:Cold Temperature / Q000009:adverse effects*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D017879:Isothiocyanates / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012677:Sensation / Q000187:drug effects / Q000502:physiology*; D012684:Sensory Thresholds / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014316:Tritium
chemical_list: C560402:A 967079; D015220:Calcium Channels; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D010091:Oximes; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C400769:TRPV2 protein, human; D050051:Transient Receptor Potential Channels; D014316:Tritium; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium