Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice

被引:110
作者
Duttaroy, A
Gomeza, J
Gan, JW
Siddiqui, N
Basile, AS
Harman, WD
Smith, PL
Felder, CC
Levey, AI
Wess, J
机构
[1] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA
[2] Univ Virginia, Dept Chem, Charlottesville, VA USA
[3] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[4] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA
关键词
D O I
10.1124/mol.62.5.1084
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M-2 and M-4 receptor subtypes, the two G(i)/G(o)-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M-2 and M-4 mAChRs [M-2/M-4 double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M-2/M-4 double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M-2 receptor single-KO mice, but retained full analgesic activity in M-4 receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M-2 and M-4 receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M-4 than for M-2 receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M-2 and M-4 mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.
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收藏
页码:1084 / 1093
页数:10
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