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Vol. 284, Issue 3, 1209-1217, March 1998
Department of Pharmacology and Toxicology, Medical College of
Virginia, Virginia Commonwealth University, Richmond, Virginia
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 
9-THC. Therefore, this
study was undertaken to determine whether its interaction with the CB1
receptor in brain was identical to that of 9-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 Bmax
values 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.
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