Sex differences and the endocannabinoid system in pain

Abstract

Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ⁹-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.

Keywords: Cannabinoids; Cannabis; Estrous cycle; Hormones; Pain; Sex differences.

Figure 1:. Mechanisms underlying sex differences in cannabinoid antinociception in rodents

Sex differences in cannabinoid antinociception in rodents have been found to vary based on a variety of factors including pain model, cannabinoid used, and effect of sex hormones, among others. The most widely studied cannabinoid, THC, has been found to be generally more potent in female rats, possibly as a function of differences in metabolism and effects of sex hormones. Abbreviations: Estradiol (E2); Progesterone (P4); Ovariectomy (OVX); WIN 55, 212-2 (WIN).

Figure 2:. Sex differences in brain endocannabinoid system expression and response

Sex differences in the expression and function of the endocannabinoid system in the brains of rodents have been found in numerous studies. Sex hormones, particularly in females, have been found to affect cannabinoid receptor expression and the affinity and efficacy of cannabinoid ligands. There have been conflicting results concerning cannabinoid receptor expression in brain regions including amygdala, cortex, and hippocampus, supporting the need for further studies. Abbreviations: Anterior (Ant.); Gonadectomy (GDX); Ovariectomy (OVX), Anandamide (AEA); 2-Arachidonylglycerol (2-AG).