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    • Previous studies have demonstrated that cannabinoid potentia

    2021-12-18

    Previous studies have demonstrated that cannabinoid potentiation of GlyR α3 subunits contributes to cannabinoid-induced analgesia. For instance, Dehydroxylcannabidiol (DH-CBD), a chemically modified cannabinoid, can alleviate acute pain and chronic inflammatory pain by targeting spinal α3 GlyRs (Xiong et al., 2012a). Additionally, cannabinoids can also act on GlyR α1 subunits (Foadi et al., 2010, Xiong et al., 2012b), which are localized in bet bromodomain areas participating in pain transmission such as brainstem and spinal cord (Baer et al., 2009, McDearmid et al., 2006, Piechotta et al., 2001), suggesting that GlyR α1 subunits may also be involved in cannabinoid analgesia. However, it's very challenging to directly explore the role of α1 GlyR in the sensation of pain because of the lack of subunit-specific agonists and antagonists. Genetically engineered animal models have been used and shown to be valuable for identifying the physiological roles of targeted genes in vivo. The previous studies revealed that a serine at 296 (S296) in the third transmembrane domain of the α1 GlyR is critical for cannabinoid potentiation (Xiong et al., 2011). To investigate the role of cannabinoid-α1 GlyR interaction in chronic pain, we have generated an GlyRα1S296A mutation knock-in mouse line. Using electrophysiological recordings and behavioral measurements, we examined the efficacy of DH-CBD potentiation of IGly in spinal slices of these mutant mice and their sensitivity to DH-CBD-induced analgesic effect in chronic pain.
    Methods
    Results
    Discussion Our study provides evidence that GlyR α1 subunit is involved in DH-CBD-induced analgesia for inflammatory pain. First, DH-CBD suppresses persistent inflammatory pain induced by subplantar injection of CFA in mice. Such a suppression by DH-CBD is blocked by the GlyR antagonist strychnine. Second, the expression level of spinal cord α1 GlyRs increases after CFA administration, suggesting an involvement of spinal α1 GlyRs during the progress of inflammatory pain. Third, the analgesic effect of DH-CBD is suppressed in the transgenic mice carrying GlyR α1 S296A mutation, which also blocks DH-CBD-induced potentiation of IGly in neurons of the spinal cord dorsal horn lamina I-II. Collectively, all these results suggest that DH-CBD relieves inflammatory pain by targeting α1 GlyRs. Additionally, this study develops a novel mouse line (GlyRα1S296A) that specifically interrupts the interaction between DH-CBD and α1 GlyRs, but does not affect the basic function of α1 GlyR. For instance, the DH-CBD-induced analgesia through α1 GlyRs is remarkably suppressed in this mouse line. Meanwhile, exaggerated startle reflex and motor disorders, due to dysfunction of α1 GlyRs (generally caused by single site mutations) (Chung et al., 2010, Harvey et al., 2008), have not been observed in the GlyRα1S296A KI mice. Thus, this mouse line can be a valuable tool for in vivo exploring the role of α1 GlyRs in some of the nonpsychotropic cannabinoid-induced behaviors in future studies. Pathological pain attracted increasing attention in the last several decades as it has been disturbing a large population of people without an effective treatment (Grace et al., 2014, Jun Chen et al., 2011, Knabl et al., 2008, Kuner, 2010). Over the past few decades, teams of researchers have been searching for novel analgesic targets, such as G-protein coupled receptors or ion channels (Daniel and Clark, 2017, St John Smith, 2017, Yekkirala et al., 2017). Harvey and his colleagues have discovered for the first time that α3 GlyR is an essential target for inflammatory pain (Harvey et al., 2008). Previous reports also indicated that cannabinoid-potentiation of α3 GlyRs contributed to cannabinoid-induced analgesic effects on chronic inflammatory and neuropathic pain (Xiong et al., 2012a). And as for α1, another essential subunit of GlyR, its role in motor function has been well studied (Kling and KochBecker, 1997, Jonathan et al., 2006, Hirzel et al., 2006). For example, mutations in the GLRA1 or GLRB genes, which encode the GlyR α1 and β subunits respectively, are the major cause of hyperekplexia/startle disease (Harvey et al., 2008, James et al., 2013, Shiang et al., 1994, Xiong et al., 2014). However, the investigation on the role of α1 subunits in pain is lacking, although α1 GlyR has already been found to localize in multiple regions in the central nervous system (CNS), such as spinal cord dorsal horn, dorsal root ganglion and rostral ventromedial medulla, which critically participate in pain perception (De Felice et al., 2011, Dib-Hajj et al., 2008, Eippert et al., 2009, King et al., 2009, Silva et al., 2013).