Sex differences in CB1 vs. CB2 receptor mediation of THC-induced antinociception

R. Craft; J. Laggart

doi:10.1016/j.jpain.2010.01.143

Cannabinoid agonists such as delta-9-tetrahydrocannabinol (THC) produce greater antinociceptive and motoric effects in female compared to male rats. The goal of the present study was to determine to what extent THC acts via CB1 or CB2 receptors in each sex. Vehicle, the CB1 antagonist SR141716A, or the CB2 antagonist SR144528 was administered i.p. to adult, gonadally intact Sprague-Dawley rats. Thirty min later, vehicle or THC (5 mg/kg) was administered i.p.; rats were then assessed on the warm water tail withdrawal, paw pressure, locomotor activity and catalepsy tests at 15-240 min post-injection. In males, THC's antinociceptive effect was dose-dependently antagonized by SR141716A (1.0-10 mg/kg) but not SR144528 (1.0-10 mg/kg), as shown in previous studies. In contrast, THC's antinociceptive effect was dose-dependently antagonized by both SR141716A and SR144528 in females. Furthermore, SR141716A was approximately 10 times more potent in females than in males: THC-induced antinociception was completely antagonized by 1.0 mg/kg in females, but required 10 mg/kg in males. THC-induced locomotor suppression was dose-dependently antagonized by SR141716A in both males and females (with greater potency in females than males), although the extent of antagonism was limited by sedative effect of SR141716A alone in both sexes. SR144528 also antagonized THC-induced locomotor suppression in females (albeit at a single dose), whereas it had no significant effect in males. Catalepsy was antagonized only by SR141716A in both sexes, though again with significantly greater potency in females than males. Thus, whereas THC acts primarily at CB1 receptors in males, it acts at both CB1 and CB2 receptors in females. Additionally, the substantial sex difference in potency of SR141716A suggests that cannabinoids may have greater affinity for CB1 receptors in females than in males. These findings may explain why females are more sensitive than males to antinociceptive and other behavioral effects of cannabinoid agonists.

Sex differences in CB1 vs. CB2 receptor mediation of THC-induced antinociception

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