Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

被引：56

作者：

Gao, Baoxi ^{[2
]}

Hierl, Markus ^{[1
,4
]}

Clarkin, Kristie ^{[3
]}

Juan, Todd ^{[3
]}

Nguyen, Hung ^{[3
]}

van der Valk, Marissa ^{[3
]}

Deng, Hong ^{[2
]}

Guo, Wenhong ^{[1
]}

Lehto, Sonya G. ^{[2
]}

Matson, David ^{[1
]}

McDermott, Jeff S. ^{[1
,2
]}

Knop, Johannes ^{[4
]}

Gaida, Kevin ^{[5
]}

Cao, Lei ^{[6
]}

Waldon, Dan ^{[6
]}

Albrecht, Brian K. ^{[7
]}

Boezio, Alessandro A. ^{[7
]}

Copeland, Katrina W. ^{[7
]}

Harmange, Jean-Christophe ^{[7
]}

Springer, Stephanie K. ^{[7
]}

Malmberg, Annika B. ^{[1
]}

McDonough, Stefan I. ^{[1
,2
]}

机构：

[1] Amgen Inc, Dept Neurosci, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Neurosci, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Prot Sci, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Lead Discovery, D-93053 Regensburg, Germany

[5] Amgen Inc, Dept Inflammat, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Dept Pharmacokinet & Drug Metab, Cambridge, MA 02142 USA

[7] Amgen Inc, Dept Chem Res & Dev, Cambridge, MA 02142 USA

来源：

PAIN | 2010年 / 149卷 / 01期

关键词：

ABT-594; Varenicline; Tropisetron; Ispronicline; SSR-180711; SSR-591813; TC-1734; TC-2696; CENTRAL-NERVOUS-SYSTEM; IN-VIVO CHARACTERIZATION; SUBSTANCE-P RECEPTOR; CORD DORSAL-HORN; RAT SPINAL-CORD; BETA; CHOLINERGIC-RECEPTORS; SYNAPTIC-TRANSMISSION; INFLAMMATORY PAIN; NEUROPATHIC PAIN;

D O I：

10.1016/j.pain.2010.01.007

中图分类号：

R614 [麻醉学];

学科分类号：

100217 ;

摘要：

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha 4b2 or for alpha 7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha 4b2 agonist ispronicline and a novel alpha 4b2-selective potentiator did not appear to produce analgesia in either model. alpha 7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha 7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha 4b2 and only minimally by alpha 7 subtypes. Taken with previous studies, the results suggest that agonism of alpha 4b2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia. (C) 2010 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

引用

页码：33 / 49

页数：17

共 128 条

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