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Vol. 62, Issue 5, 1084-1093, November 2002

Evaluation of Muscarinic Agonist-Induced Analgesia in Muscarinic Acetylcholine Receptor Knockout Mice

Alokesh Duttaroy,1 Jesus Gomeza, Jai-Wei Gan, Nasir Siddiqui, Anthony S. Basile, W. Dean Harman, Philip L. Smith, Christian C. Felder, Allan I. Levey, and Jürgen Wess

Laboratory of Bioorganic Chemistry, National Institute of Diabetes Digestive and Kidney Diseases, Bethesda, Maryland (A.D., J.G., J.-W.G., N.S., A.S.B., J.W.); Department of Chemistry, University of Virginia, Charlottesville, Virginia (W.D.H., P.L.S.); Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana (C.C.F.); and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia (A.I.L.)

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 M2 and M4 receptor subtypes, the two Gi/Go-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M2 and M4 mAChRs [M2/M4 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 M2/M4 double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M2 receptor single-KO mice, but retained full analgesic activity in M4 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 M2 and M4 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 M4 than for M2 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 M2 and M4 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.

1 Current address: Human Genome Sciences, Inc., Rockville, MD 20850.

Copyright © 2002 by U.S. Government


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