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Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.
Pain. 2011 May; 152(5):1165-1172.PAIN

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+Show Affiliations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21402443

Citation

Chen, Jun, et al. "Selective Blockade of TRPA1 Channel Attenuates Pathological Pain Without Altering Noxious Cold Sensation or Body Temperature Regulation." Pain, vol. 152, no. 5, 2011, pp. 1165-1172.
Chen J, Joshi SK, DiDomenico S, et al. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain. 2011;152(5):1165-1172.
Chen, J., Joshi, S. K., DiDomenico, S., Perner, R. J., Mikusa, J. P., Gauvin, D. M., Segreti, J. A., Han, P., Zhang, X. F., Niforatos, W., Bianchi, B. R., Baker, S. J., Zhong, C., Simler, G. H., McDonald, H. A., Schmidt, R. G., McGaraughty, S. P., Chu, K. L., Faltynek, C. R., ... Kym, P. R. (2011). Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain, 152(5), 1165-1172. https://doi.org/10.1016/j.pain.2011.01.049
Chen J, et al. Selective Blockade of TRPA1 Channel Attenuates Pathological Pain Without Altering Noxious Cold Sensation or Body Temperature Regulation. Pain. 2011;152(5):1165-1172. PubMed PMID: 21402443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. AU - Chen,Jun, AU - Joshi,Shailen K, AU - DiDomenico,Stanley, AU - Perner,Richard J, AU - Mikusa,Joe P, AU - Gauvin,Donna M, AU - Segreti,Jason A, AU - Han,Ping, AU - Zhang,Xu-Feng, AU - Niforatos,Wende, AU - Bianchi,Bruce R, AU - Baker,Scott J, AU - Zhong,Chengmin, AU - Simler,Gricelda H, AU - McDonald,Heath A, AU - Schmidt,Robert G, AU - McGaraughty,Steve P, AU - Chu,Katharine L, AU - Faltynek,Connie R, AU - Kort,Michael E, AU - Reilly,Regina M, AU - Kym,Philip R, Y1 - 2011/03/12/ PY - 2010/01/27/received PY - 2010/12/21/revised PY - 2011/01/24/accepted PY - 2011/3/16/entrez PY - 2011/3/16/pubmed PY - 2011/8/24/medline SP - 1165 EP - 1172 JF - Pain JO - Pain VL - 152 IS - 5 N2 - 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. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/21402443/Selective_blockade_of_TRPA1_channel_attenuates_pathological_pain_without_altering_noxious_cold_sensation_or_body_temperature_regulation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/00006396-201105000-00031 DB - PRIME DP - Unbound Medicine ER -