A preliminary investigation of the mechanisms underlying cannabinoid tolerance in the mouse vas deferens

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Vasa deferentia taken from mice treated with Δ 9-tetrahydrocannabinol (20 mg/kg i.p., once daily for 2 days) showed tolerance to the inhibitory effect of the cannabinoid, R-(+)-arachidonyl-1′-hydroxy-2′-propylamide, on electrically evoked twitches. This treatment did not induce tolerance to the inhibitory effects on the twitch response of morphine or clonidine or of selective μ-, δ- or κ-opioid receptor agonists. Nor did it affect the contractile potencies of noradrenaline or β,γ-methylene- l-ATP. We suggest that cannabinoid tolerance in the vas deferens is attributable neither to downregulation of opioid receptors or α 2-adrenoceptors nor to an increased sensitivity of this tissue to its main contractile transmitters noradrenaline and ATP. A concentration of Δ 9-tetrahydrocannabinol that inhibits electrically evoked twitches of the vas deferens (100 nM) did not alter the ability of noradrenaline or β,γ-methylene- l-ATP to induce contractions suggesting that Δ 9-tetrahydrocannabinol inhibits the twitch response by acting prejunctionally.