Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA.
Pain. 2013 Sep;154(9):1709-1717. doi: 10.1016/j.pain.2013.05.017. Epub 2013 May 15.
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.
大麻素激动剂，如 Δ(9)-四氢大麻酚（THC），在使用急性疼痛模型时，在雌性大鼠中比在雄性大鼠中更有效。我们测试了这样一个假设，即 THC 在雌性大鼠中比在雄性大鼠中更有效，使用一种更持久的、炎症性疼痛模型。在完全弗氏佐剂（CFA）注射到后爪后 1、3 和 7 天，检查了 THC 的抗痛觉过敏、抗痛觉过敏和抗水肿作用。腹腔内（i.p.）给予的系统 THC（0.32-3.2mg/kg，每天相同剂量）在减轻 CFA 诱导的热痛觉过敏方面在雌性大鼠中比在雄性大鼠中更有效，但在雌性大鼠中也更镇静。当局部给予发炎的后爪时，THC（250-500μg 足底内，i.pl.）在两性中均不影响运动活动，但在雌性大鼠中产生更大的抗痛觉过敏和抗痛觉过敏作用。尽管 THC 在雌性大鼠中具有更大的抗痛觉过敏和抗痛觉过敏作用，但 i.p.和 i.pl. THC 都使雄性大鼠的后爪厚度（水肿）减少更多。两种性别中，i.p. THC 的抗痛觉过敏作用都被 CB1 受体选择性拮抗剂利莫那班阻断。同样，i.pl. 利莫那班也拮抗了 i.pl. THC 在两性中的作用；相反，CB2 拮抗剂 SR144528 仅在雌性大鼠中显著减弱了 i.pl. THC 的抗痛觉过敏作用。足底内的 SR144528 也拮抗了 i.pl. THC 在雄性大鼠中的抗水肿作用。这项研究表明，大麻素可能更擅长减少雄性大鼠的水肿，而对雌性大鼠的炎症性疼痛更有效。此外，THC 对炎症性疼痛的外周作用的性别差异可能是由于雌性大鼠中两种类型的大麻素受体的激活，而雄性大鼠中主要是 CB1 受体。
