A PRELIMINARY INVESTIGATION OF THE MECHANISMS UNDERLYING CANNABINOID TOLERANCE IN THE MOUSE VAS-DEFERENS

Vasa deferentia taken from mice treated with Delta(9)-tetrahydrocannab inol (20 mg/kg i.p., once daily for 2 days) showed tolerance to the in hibitory effect of the cannabinoid, R-(+)-arachidonyl-1'-hydroxy-2'-pr opylamide, on electrically evoked twitches. This treatment did not ind uce tolerance to the inhibitory effects on the twitch response of morp hine or clonidine or of selective mu-, delta- or kappa-opioid receptor agonists. Nor did it affect the contractile potencies of noradrenalin e or beta,gamma-methylene-L-ATP. We suggest that cannabinoid tolerance in the vas deferens is attributable neither to downregulation of opio id receptors or alpha(2)-adrenoceptors nor to an increased sensitivity of this tissue to its main contractile transmitters noradrenaline and ATP. A concentration of Delta(9)-tetrahydrocannabinol that inhibits e lectrically evoked twitches of the vas deferens (100 nM) did not alter the ability of noradrenaline or beta,gamma-methylene-L-ATP to induce contractions suggesting that Delta(9)-tetrahydrocannabinol inhibits th e twitch response by acting prejunctionally.