Abstract

The purpose of this study was to determine whether sex differences in cannabinoid-induced antinociception and motoric effects can be attributed to differential activation of CB1 or CB2 receptors. Rats were injected i.p. with vehicle, rimonabant (SR141716A, 0.1-10 mg/kg, a putative CB1 receptor-selective antagonist) or SR144528 (1.0-10 mg/kg, a putative CB2 receptor-selective antagonist). Thirty min later, ∆9-tetrahydrocannabinol (THC, 1.25-40 mg/kg) or CP55,940 (0.05-1.6 mg/kg) was injected. Paw pressure and tail withdrawal antinociception, locomotor activity and catalepsy were measured. Rimonabant dose-dependently antagonized THC and CP55,940 in each test, but was up to 10 times more potent in females than males on the nociceptive tests; estimates of rimonabant affinity (apparent pKB) for the CB1 receptor were approximately 0.5-1 mol/kg higher in females than males. SR144528 partially antagonized THC-induced tail withdrawal antinociception and locomotor activity in females, but this antagonism was not dose-dependent or consistent; no SR144528 antagonism was observed in either sex tested with CP55,940. Neither the time course of rimonabant antagonism nor plasma levels of rimonabant differed between the sexes. Rimonabant and SR144528 did not antagonize morphine-induced antinociception, and naloxone did not antagonize THC-induced antinociception in either sex. These results suggest that THC produces acute antinociceptive and motoric effects via activation of CB1 - and perhaps under some conditions, CB2 receptors - in females, whereas THC acts primarily at CB1 receptors in males. Higher apparent pKB for rimonabant in females suggests that cannabinoid drugs bind with greater affinity to CB1 receptors in females than males, likely contributing to greater antinociceptive effects observed in female compared to male rats.