THC decreases edema more in male rats but is more effective against inflammatory pain in females. Sex differences in THC's peripheral effects against inflammatory pain may be a result of activation of CB1 and CB2 receptors in females, in contrast to primarily CB1 receptors in males.
Cannabinoid agonists such as Δ9-tetrahydrocannabinol (THC) are more potent and/or efficacious antinociceptive agents in female than male rats using acute pain models. We tested the hypothesis that THC is more effective in females than males using a model of longer-lasting, inflammatory pain. THC's anti-allodynic, anti-hyperalgesic, and anti-edema effects were examined 1, 3, and 7 days after injection of complete Freund's adjuvant (CFA) into the hind paw. Systemically administered THC (0.32–3.2 mg/kg, intraperitoneally [i.p.], same dose each day) was significantly more effective in females than males in attenuating CFA-induced thermal hyperalgesia, but was also more sedative in females. When administered locally into the inflamed hind paw, THC (250–500 μg intraplantar, i.pl.) did not affect locomotor activity in either sex, yet produced greater anti-allodynic and anti-hyperalgesic effects in females than males. Despite THC's greater anti-allodynic and anti-hyperalgesic effects in females, both i.p. and i.pl. THC reduced hind paw thickness (edema) more in males. The anti-hyperalgesic effect of i.p. THC was blocked by the CB1 receptor-selective antagonist rimonabant in both sexes. Similarly, i.pl. rimonabant antagonized i.pl. THC's effects in both sexes; in contrast, the CB2 antagonist SR144528 significantly attenuated i.pl. THC's anti-allodynic effect only in females. Intraplantar SR144528 also antagonized i.pl. THC's anti-edema effect in males. This study suggests that cannabinoids may be better at reducing edema in males while being more effective against inflammatory pain in females. Furthermore, sex differences in THC's peripheral effects against inflammatory pain may be a result of activation of both types of cannabinoid receptors in females, in contrast to predominantly CB1 receptors in males.