*6.3. Endocannabinoid Receptors*

The first biologically active component of cannabis was identified in the 1960s as delta-9-tetrahydrocannabinol (THC), a potent drug classified as a sedative-hypnotic. This was followed by the discovery of two cannabinoid receptors, cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R), in the early 1990s. Both are G-protein-coupled receptors and serve as the primary sites of action for THC. Together, they are involved in the major neuromodulatory endocannabinoid system (ECS), whose primary goal is to promote homeostasis [68]. The ECS is widespread, and CB1Rs are found throughout the central nervous system and some peripheral tissues, while CB2Rs are primarily found in peripheral tissues and immune cells [69]. Cannabinoids act on receptors other than CB1R and CB1R. They modulate transient receptor potential (TRP) channels, including TRP vanilloid (TRPV) channels, which are involved in neuropathic pain signals in EM [70].

There is a broad range of mechanisms by which cannabinoids modulate pain, and given the high impact of EM on women's quality of life such as the high prevalence of EM, cannabinoid-mediated effects on EM-related pain have become a subject of inquiry [68,69].

Different categories of EM pain may be modulated by cannabinoids [71,72]. There is evidence that a disruption of the normal ECS potentiates pain in EM patients. In women with EM, decreased CB1R expression compared to controls and increased anandamide (AEA) and 2-arachidonoylglycerol (2-AG) expression, both endogenous ligands of the CB1R and CB2R, are consistent with a negative feedback loop that is permissive of inflammation [68].

In vitro studies have shown that exogenous cannabinoids could correct these dysregulations. When endometrial cells were treated with cannabinoid agonist WIN 5512-2, the result was decreased cell proliferation, decreased reactive oxygen species production, and reduction in alpha-smooth muscle actin expression, lending supporting evidence to the anti-inflammatory effects of cannabinoids [73]. Bilgic et al. [74] also found that CB1R and CB2R expressions are decreased in EM tissue compared to control, with concurrently decreased apoptosis indexes. The same study found that exposure of EM tissue to CB1R and CB2 agonists resulted in pro-apoptotic effects. However, animal model studies have shown divergent results. A nude mouse model of transplanted human deep infiltrating EM confirmed the antiproliferative effects of cannabinoids on the growth of deep infiltrating lesions [64]. In contrast, in a mouse analogue of early-stage EM, the activation resulted in an increased disease burden [75]. The complexity of the ECS superimposed on the two different mouse models used may account for the different results [76].

Endocannabinoids have also been shown to trigger endometrial cell migration [77]. Moreover, CB1Rs have been found on the sensory and sympathetic neurons innervating EM lesions [78]. Given the above role of the ECS in the EM modulation, cannabinoids have been proposed as a putative therapy. In fact, an Australian cross-sectional survey showed that self-management strategies were very common in EM patients and that cannabis and cannabis products were among the most effective at pain reduction [79].
