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    • Combretastatin A4 The GPR receptor is also emerging

    2022-09-09

    The GPR55 receptor is also emerging as an important therapeutic target. GPR55−/− mice possess no overt phenotype, but were protected in models of inflammatory and neuropathic pain (Staton et al., 2008). Staton et al. (2008) reported that no GPR55 mRNA could be detected by RT-PCR in the animals. Also the levels of CB1 and CB2 mRNA were unchanged in the Combretastatin A4 and spleen, respectively, indicating that compensatory changes in these two receptors did not occur in the mice. Female GPR55−/− did display a reduction in withdrawal latency in an acute pain model, the hot water tail flick latency test, when tested at 50°C, but not at higher temperatures (52.5°C and 55°C). A more robust difference was seen in two models of hyperalgesia (Staton et al., 2008). In mechanical hyperalgesia induced by intraplantar administration of Freund's complete adjuvant (FCA), inflammatory mechanical hyperalgesia was completely absent in both male GPR55 KO mice, up to 14days post-injection, and female GPR55−/− mice for one day post-FCA. In the partial nerve ligation model of neuropathic hypersensitivity, GPR55−/− mice of both sexes failed to develop mechanical hyperalgesia up to 28days post-ligation. Cytokine profiling experiments showed increased levels of IL-4, IL-10, IFN γ and GM-CSF in paws from the FCA-injected GPR55−/− mice when compared with the FCA-injected GPR55 wild-type mice. While this profile is a mixture of anti-inflammatory (IL-4 and IL-10) and inflammatory (IFN-gamma and GM-CSF) cytokines, it suggests that GPR55 signaling can influence the regulation of certain cytokines which may contribute to the lack of inflammatory mechanical hyperalgesia in the GPR55−/− mice. Altogether, these data suggest that GPR55 antagonists may have therapeutic potential in the treatment of both inflammatory and neuropathic pain. GPR55 affects osteoclast and osteoblast differentiation to influence bone mass (Whyte et al., 2009). In this study, where receptor knockout mice were generated by deletion of the entire coding region of GPR55 by homologous recombination, male GPR55−/− mice had increased numbers of morphologically inactive osteoclasts resulting in a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage (Whyte et al., 2009). In sum, this report indicated a role for GPR55 in bone resorption, and suggested that CBD and GPR55 antagonists may be useful for the treatment of osteoporosis (Whyte et al., 2009). Recent studies have also suggested a role for GPR55 in the development of cancer, To date, three studies indicate that GPR55 activation is pro-carcinogenic (Andradas et al., 2011, Ford et al., 2010, Pineiro et al., 2011); and one study suggests that GPR55 activation may in fact be anticarcinogenic (Huang et al., 2011). Thus, further studies need to be performed to delineate whether GPR55 agonists or antagonists might be useful as chemotherapeutics.
    Future directions The continued characterization of GPR55 and GPR35 are important for understanding their physiological roles. It is tempting to speculate that GPR55 is an “anti-cannabinoid” receptor, as its pharmacology is somewhat opposite that of CB1. Because of the overlapping ligand profile with the CB1 cannabinoid receptor, it will be important to determine the role of this receptor in drug addiction. GPR35 appears to be important in nociception, at least in anti-inflammatory models of pain. Modulation of the conversions among 2-arachidonoyl LPA, 2-arachidonoyl LPI and 2-AG would be a major contribution factor for available ligands for the GPR35, GPR55 and CB receptors. However, these ligand conversions are not been fully understood. Hence, it is essential to know which enzyme proteins underlie the conversion reactions, especially the conversions from 2-AG to 2-arachidonoyl LPI and 2-arachidonoyl LPA to 2-arachidonoyl LPI, as these may dictate which receptors are subsequently activated (Fig. 2). Thus far, no information is available regarding this issue. It is also important to know whether there is a direct metabolic relationship between the two types of structurally related ligands, 2-arachidonoyl LPA (GPR35 ligand) and 2-AG (cannabinoid receptor ligand). Such information would be a great help in better understanding the metabolism and physiological roles of these natural ligands. The mechanisms underlying the direct link or crosstalk between GPR35, GPR55, cannabinoid receptor and the lysophospholipid receptor systems should be considered and elucidated in future studies.