Abstract
Anandamide is the newly discovered endogenous cannabinoid ligand that binds to brain cannabinoid receptors and shares most, but not all, of the pharmacological properties of Δ9-THC. Therefore, this study was undertaken to determine whether its interaction with the CB1 receptor in brain was identical to that of Δ9-THC. Anandamide depressed spontaneous activity and produced hypothermia, antinociception and immobility in mice after i.v. administration. However, none of these effects was blocked by pretreatment with the selective CB1 antagonist, SR 141716A. However, the metabolically stable analog 2-methyl-2′-fluoroethylanandamide produced reductions in motor activity and antinociception in mice, effects that were blocked by the antagonist. To determine whether anandamide’s receptor binding mimicked that of other cannabinoids, an autoradiographic comparison of anandamide, SR 141716A and CP 55,940 competition for [3H]CP55,940 binding was conducted throughout rat brain. The receptor affinities for all three compounds did not change according to brain area. As expected, Bmax values differed dramatically among differ brain areas. However, the Bmaxvalues for each brain area were similar regardless of the compound used for displacement. These data suggest that anandamide, SR 141716A and CP 55,940 compete for the same cannabinoid receptor throughout brain despite SR 141716A’s failure to block anandamide’s pharmacological effects. Although there is no question that anandamide binds to the cannabinoid receptor, failure of SR 141716A to block its pharmacological effects in mice poses a dilemma. The results presented herein raise the possibility that anandamide may not be producing all of its effects by a direct interaction with the CB1 receptor.
Footnotes
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Send reprint requests to: Dr. Billy R. Martin, Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, MCV Station, Richmond, VA 23298-0613.
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↵1 This work was supported by NIDA Grants DA 03672, DA 09789, DA 08677 and DA 07027 (training grant for I.B.A.).
- Abbreviations:
- BSA
- bovine serum albumin
- CP 55
- 940, (−)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxyl propyl] cyclohexan-1-ol
- HU-243
- 11-hydroxyhexahydrocannabinol-3-dimethylheptyl
- nor-BNI (nor-binaltorphimine)
- PEI, polyethylenimine
- PMSF
- phenylmethylsulfonyl fluoride
- THC
- tetrahydrocannabinol
- SR141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide
- Received April 25, 1997.
- Accepted November 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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