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PB Smith, DR Compton, SP Welch, RK Razdan, R Mechoulam and BR Martin
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
The arachidonic acid derivative anandamide (arachidonylethanolamide) has been isolated from porcine brain and has been shown to bind competitively to the cannabinoid receptor. Although the pharmacological activity of this compound has not yet been fully determined, preliminary data suggest that it produces several effects similar ot the cannabinoids. In the present experiments anandamide produced effects similar to those of delta 9-tetrahydrocannabinol, including antinociception (as determined in a latency to tail-flick evaluation), hypothermia, hypomotility and catalepsy in mice after i.v., i.t. and i.p. administration. In general, the effects of anandamide occurred with a rapid onset, but with a rather short duration of action. Prominent antinociceptive effects (> 80% maximal possible effect) were measured immediately after i.v. and i.t. administration. Anandamide produced significant decreases in rectal temperature (2-4 degrees C) after either i.v. or i.t. injection. Maximal effects on motor activity (approximately 85% inhibition) were observed immediately after i.v. and i.p. administration and 10 min after i.t. administration. Maximum immobility observed after i.v. administration was over 80%, yet that produced after i.p. and i.t. administration was too small (< or = 20%) to be considered pharmacologically relevant. Anandamide was less potent (1.3 to 18 times) than delta 9-tetrahydrocannabinol in all behavioral assays. Pretreatment with nor-binaltorphimine, a kappa opioid antagonist which blocks i.t. delta 9-tetrahydrocannabinol-induced antinociception, failed to alter antinociception after i.t. anandamide administration. Binding studies demonstrating that anandamide displaces [3H]CP-55,940 from rat whole brain P2 membrane preparations with a KD of 101 +/- 15 nM. These findings demonstrate that anandamide produces effects in a tetrad of tests used to predict cannabimimetic activity and supports the contention of its role as an endogenous cannabinoid ligand. However, there appear to be distinct differences between anandamide and the cannabinoids with regard to their antinociceptive properties, and other properties vary as a function of route of administration.
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