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    • The endocannabinoid system ECS consists of cannabinoid

    2022-06-27

    The endocannabinoid system (ECS) consists of cannabinoid (CB)1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonylglycerol, and the synthesizing and degrading enzymes for these ligands. Cannabinoids and the ECS are involved in the regulation of GI motility in physiological and pathophysiological conditions (Izzo et al., 2001; Massa et al., 2005; Storr et al., 2008; Pertwee et al., 2010). In particular, the involvement of the cannabinoid receptors CB1 and CB2 and the endocannabinoid degrading enzymes fatty Ro3306 amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) has been reported (Pinto et al., 2002; Duncan et al., 2008; Storr et al., 2009). In the last two decades, in vitro and in vivo studies have revealed roles for both central and peripheral CB receptors in the control of GI motility (Coutts and Izzo, 2004; Izzo et al., 2001; Storr and Sharkey, 2007). Interestingly, not all cannabinoid effects on GI motility can be explained by actions on CB1 and CB2 receptors and numerous additional sites of actions have been suggested. These include transient receptor potential vanilloid 1 (TRPV1) receptors, peroxisome proliferator-activated receptor-alpha (PPARα) and cyclooxygenase-2 (COX-2) inhibition (Pertwee et al., 2010; Piomelli, 2003). Recently, an orphan G protein-coupled receptor 55 (GPR55) was shown to be a binding site for cannabinoids and became a likely candidate for mediating some of the previously unexplained non-CB1, non-CB2 effects induced by certain cannabinoids (Moriconi et al., 2010; Pertwee, 2007; Ross, 2009). Radioligand binding studies demonstrated GPR55 binding for both endocannabinoids and synthetic cannabinoids that may also be agonists or antagonists at CB1 or CB2 receptors, or both. The atypical synthetic cannabinoid O-1602 was found to activate GPR55 with negligible binding to CB1 and CB2 and is considered as a selective GPR55 agonist (Ryberg et al., 2007; Whyte et al., 2009; Johns et al., 2007; Schicho et al., 2010). Recent data from a transgenic GPR55−/− mouse model further supports O-1602 as a GPR55 agonist (Whyte et al., 2009). Little information is available on antagonists at the GPR55 receptor, although cannabidiol (CBD) appears to be a selective GPR55 receptor antagonist (Pertwee, 2007; Ryberg et al., 2007; Whyte et al., 2009; Thomas et al., 2007). Localization of GPR55 is rarely studied. However, convincing data shows that GPR55 mRNA is expressed in the brain (Sawzdargo et al., 1999). The GPR55 activation was reported to have effects on osteoclast function, bone density and cancer cell proliferation, but surprisingly there is no conclusive information yet available shedding light on the localization and function of GPR55 in the gastrointestinal (GI) tract (Whyte et al., 2009; Sawzdargo et al., 1999; Pineiro et al., 2010; Andradas et al., 2010; Lin et al., 2011). The present study aimed at identifying whether GPR55 is expressed in the GI tract and where it is localized. We also investigated the role of the GPR55 receptor in the regulation of mouse GI motility in vitro and in vivo, utilizing a selective GPR55 agonist, O-1602 and the antagonist, CBD. The effects were further analysed employing a well-characterized cannabinoid receptor agonist WIN55,212-2 and selective CB1 and CB2 antagonists. The involvement of respective receptors in the action of O-1602 and CBD was also studied in the CB1/2−/− and GPR55−/− mice. Finally, the action of GRP55-selective compounds in the central nervous effects was characterized.
    Material and methods
    Results
    Discussion The ECS is involved in the regulation of GI motility under physiological and pathophysiological conditions. The discovery of new elements of the ECS is of particular interest, since it sets the stage for the development of the therapeutic potential of the system (Schicho and Storr, 2010). However, the usefulness of targeting the ECS is presently limited by psychotropic side effects of CB1 receptor agonists or antagonists (Schicho and Storr, 2011). The recent discovery that some cannabinoids exert strong binding at the GPR55 receptor and the observation that GPR55 exhibits a number of key differences in comparison with classical CB receptors has sparked considerable interest in this novel cannabinoid binding site (Johns et al., 2007; Sharir and Abood, 2010). In the present study we have identified a previously unknown distribution and function of GPR55 in the GI tract of mice and humans, which may be crucial for the future use of GPR55 agonists in the clinical treatment of IBS and other FGIDs associated with GI hypermotility.