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PNAS 100 (18): 10529-10533

Copyright © 2003 by the National Academy of Sciences.


Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Mohab M. Ibrahim*, Hongfeng Deng{dagger}, Alexander Zvonok{dagger}, Debra A. Cockayne{ddagger}, Joyce Kwan{ddagger}, Heriberto P. Mata§, Todd W. Vanderah, Josephine Lai, Frank Porreca, Alexandros Makriyannis{dagger},||, and T. Philip Malan, Jr.§,||

*Interdisciplinary Graduate Program in Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85724; {dagger}Center for Drug Discovery, Departments of Medicinal Chemistry and Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269-2092; {ddagger}Neurobiology Unit, Roche Bioscience, Palo Alto, CA 94304; and Departments of §Anesthesiology and Pharmacology, University of Arizona College of Medicine, Tucson, AZ 85724

Received for publication May 7, 2003.

Abstract: We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1-/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.

|| To whom correspondence may be addressed at: (T.P.M.) Department of Anesthesiology, University of Arizona, P.O. Box 245114, Tucson, AZ 85724-5114. E-mail: malan{at}; or (A.M.) Center for Drug Discovery, University of Connecticut, 372 Fairfield Road, U-2092, Storrs, CT 06269-2092. E-mail: makriyan{at}

Communicated by John H. Law, University of Arizona, Tucson, AZ, July 9, 2003

Abbreviation: SNL, spinal nerve ligation.

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