Cannabinoid agonists such as Δ(9)-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 (0.32-3.2mg/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.