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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


Figure 3
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Fig. 3. (A) Generation of CB1 receptor-deficient mice. (B) Disruption of the CB1 receptor gene eliminated binding of the nonselective cannabinoid ligand [3H]CP55,940. Shown is autoradiography of 10 nM [3H]CP55,940 binding in CB1+/+ and CB1-/- sagittal sections of mouse brain (Top and Middle) and transverse sections of lumbar spinal cord (Bottom).

 

Figure 1
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Fig. 1. AM1241 is a CB2 cannabinoid receptor-selective ligand. (A) Structure of AM1241. (B) Equilibrium-competition binding of AM1241 vs. [3H]CP55,940 using either rat brain synaptosomal membranes (CB1) or mouse spleen homogenates (CB2) illustrates the selectivity of this ligand for CB2. The curves shown are representative of single experiments that were independently replicated three times.

 

Figure 2
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Fig. 2. AM1241 dose-dependently inhibits sensory hypersensitivity in rats. (A) Inhibition of tactile hypersensitivity. (B) Inhibition of thermal hypersensitivity. BL, presurgical baseline; SNL, after spinal nerve ligation. All drugs were administered i.p. AM630 and AM251 were administered at a dose of 300µg/kg. Data are expressed as mean ± SEM; n = 6 per group. #, P < 0.05 compared with presurgical baseline; +, P < 0.05 compared with AM1241 alone.

 

Figure 4
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Fig. 4. AM1241 inhibits tactile hypersensitivity in mice lacking the CB1 receptor. (A) Sham-operated wild-type mice. (B) Spinal nerve-ligated wild-type mice. (C) Sham-operated CB1-/- mice. (D) Spinal nerve-ligated CB1-/- mice. BL, presurgical baseline; S, after sham operation; SNL, after spinal nerve ligation. Doses used were as follows: AM1241, 1 mg/kg; AM 630, 1 mg/kg; AM251, 300 µg/kg. Data are expressed as mean ± SEM; n = 6 per group. #, P < 0.05 compared with presurgical baseline; *, P < 0.05 compared with postsurgical values; +, P < 0.05 compared with AM1241 alone.

 

Figure 5
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Fig. 5. AM1241 inhibits thermal hypersensitivity in mice lacking the CB1 receptor. (A) Sham-operated wild-type mice. (B) Spinal nerve-ligated wild-type mice. (C) Sham-operated CB1-/- mice. (D) Spinal nerve-ligated CB1-/- mice. BL, presurgical baseline; S, after sham operation. SNL, after spinal nerve ligation. Doses used were as follows: AM1241, 3 mg/kg; AM 630, 1 mg/kg; AM251, 300 µg/kg. Data are expressed as mean ± SEM; n = 6 per group. #, P < 0.05 compared with presurgical baseline; *, P < 0.05 compared with postsurgical values; +, P < 0.05 compared with AM1241 alone.

 


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