Testosterone is required for the regulation of cannabinoid receptors in trigeminal ganglia under inflammatory conditions, which explains sex differences in the antihyperalgesic effects of peripherally administered cannabinoids.
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.
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Program in Neuroscience, Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD 21201, USA
*Corresponding author. Address: Department of Neural and Pain Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA. Tel.: +1 410 706 6027; fax: +1 410 706 4172.
Article history: Received 19 March 2012; Received in revised form 31 July 2012; Accepted 31 July 2012.