Sex differences in cannabinoid and opioid mediated analgesia

Abstract

Orofacial musculoskeletal pain conditions, such as temporomandibular disorder (TMD), are debilitating and often difficult to treat. As with many chronic pain conditions, TMD occurs more frequently in women. Thus, understanding mechanisms underlying sex differences in pain and analgesia is essential for effective pain management in both sexes. This study introduces the potential therapeutic advantage of targeting cannabinoid 1 receptor (CB1) localized in primary afferent neurons under myositis conditions. Although sex differences in CB1 responses are recognized in the CNS, it is not known whether such sex differences exist in the periphery. Therefore, I investigated whether peripheral cannabinoid treatment leads to sex differences in anti-hyperalgesic effects, and whether the effects are mediated by sex differences in CB1 level in trigeminal ganglia (TG) under a rodent orofacial myositis model. Peripherally administered ACPA, a specific CB1 agonist, significantly attenuated inflammation-induced mechanical hypersensitivity in the masseter of male rats. In female rats, a 30-fold higher dose of ACPA was required to produce a reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly up-regulated CB1 mRNA expression in TG from males, but not from females, and CB1 mRNA levels in TG were positively correlated with the anti-hyperalgesic effect of ACPA. IL-1β and IL-6, elevated in the muscle tissue following inflammation, induced a significant up-regulation of CB1 mRNA expression in TG cultures from male rats. The up-regulation of CB1 was prevented in TG cultures from orchidectomized males, and was restored by testosterone treatment. The cytokines did not alter the CB1 mRNA level in TG from intact or ovariectomized female rats. Neither estradiol nor estrogen receptor blockade had any effect on CB1 expression. Similar results were obtained regarding cytokine-induced regulation of μ-opioid receptor (MOR) in TG, another important peripheral target for pain management. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1 and MOR in TG under inflammatory conditions, which explains the sex differences in the anti-hyperalgesic effects of peripherally administered agonists. These data offer important new insights for the development of mechanism-based sex-specific pharmacological treatment alternatives that can be directed at the peripheral anti-nociceptive systems to ameliorate persistent pain.