Program in Neuroscience, Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD 21201, USA.
Pain. 2012 Nov;153(11):2283-2291. doi: 10.1016/j.pain.2012.07.037. Epub 2012 Aug 31.
In this study, we assessed the effects of peripherally administered cannabinoids in an orofacial myositis model, and the role of sex hormones in cannabinoid receptor (CBR) expression in trigeminal ganglia (TG). Peripherally administered arachidonylcyclopropylamide (ACPA), a specific CB1R agonist, significantly attenuated complete Freund's adjuvant (CFA)-induced mechanical hypersensitivity in the masseter muscle in male rats. The ACPA effect was blocked by a local administration of AM251, a specific CB1R antagonist, but not by AM630, a specific CB2R antagonist. In female rats, a 30-fold higher dose of ACPA was required to produce a moderate reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly upregulated CB1R mRNA expression in TG in male, but not in female, rats. There was a close correlation between the CB1R mRNA levels in TG and the antihyperalgesic effect of ACPA. Interleukin (IL)-1β and IL-6, which are elevated in the muscle tissue following CFA treatment, induced a significant upregulation of CB1R mRNA expression in TG from male rats. The upregulation of CB1R was prevented in TG cultures from orchidectomized male rats, which was restored by the application of testosterone. The cytokines did not alter the CB1R mRNA level in TG from intact as well as ovariectomized female rats. Neither estradiol supplement nor estrogen receptor blockade had any effects on CB1R expression. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1Rs in TG under inflammatory conditions, which provide explanations for the sex differences in the antihyperalgesic effects of peripherally administered cannabinoids.
在这项研究中，我们评估了外周给予大麻素在口面肌炎模型中的作用，以及性激素在三叉神经节（TG）中大麻素受体（CBR）表达中的作用。外周给予花生四烯基环丙基酰胺（ACPA），一种特异性 CB1R 激动剂，显著减轻了雄性大鼠咬肌中完全弗氏佐剂（CFA）诱导的机械性超敏反应。ACPA 的作用被局部给予 AM251，一种特异性 CB1R 拮抗剂阻断，但不被 AM630，一种特异性 CB2R 拮抗剂阻断。在雌性大鼠中，需要 30 倍更高剂量的 ACPA 才能产生中度降低机械性超敏反应。CFA 注射到咬肌中，显著上调了雄性大鼠 TG 中的 CB1R mRNA 表达，但在雌性大鼠中没有上调。TG 中 CB1R mRNA 水平与 ACPA 的抗痛觉过敏作用密切相关。白细胞介素（IL）-1β和 IL-6 在 CFA 处理后肌肉组织中升高，诱导 TG 中 CB1R mRNA 表达显著上调，雄性大鼠。在去势雄性大鼠的 TG 培养物中，这种上调被阻断，但在应用睾酮后得到恢复。这些细胞因子没有改变完整和卵巢切除雌性大鼠 TG 中 CB1R mRNA 水平。雌二醇补充或雌激素受体阻断均对 CB1R 表达没有影响。这些数据表明，在炎症条件下，睾丸酮而非雌二醇是调节 TG 中 CB1R 的必需物质，这为外周给予大麻素的抗痛觉过敏作用中的性别差异提供了解释。
