So science has proven that morphine damages the cannabinoid system and cannaboids enhances the morphine system.
The endogenous cannabinoid system (ECS), formed by cannabinoid receptors, lipid-derived endogenous ligands, and enzymes that synthesize and degrade the endogenous ligands, has recently been implicated in the process of rewarding behavior formation mediated by the mesolimbic circuitry. As it was shown previously, the blockade of cannabinoid receptor 1 (CB1R) in the VTA or NAc significantly suppressed morphine-induced conditioned place preference (CPP) or heroin self-administration (Caillé and Parsons, 2006; Rashidy-Pour et al., 2013); while administration of a selective Cannabinoid receptor 2 (CB2R) agonist JWH015 effectively attenuated acute morphine-induced dopamine release in the NAc, as well as attenuated morphine-induced rewarding behavior when co-administered with morphine (Grenald et al., 2017).
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.632757/full
So the question of this study is how does opioid use change the endocannabinoid system:
endopeptidase inhibitors are the most affected proteins in the VTA following repeated morphine treatment (All 14 proteins were reduced significantly and 11 of them had over 2-fold reduction in expression; Figures 1E, F; Supplementary Table S3). α-1-macroglobulin was the most significantly affected protein out of all 3,680 proteins, which has the largest fold change loss after morphine treatment of all the significantly affected proteins related to endopeptidase activity (labeled red in Figure 1F).
In the proteomic analysis, 31 endogenous cannabinoid system-related proteins were detected in the VTA (Table 1). Two of these proteins, phospholipase Cγ-2 (PLCγ2) and α/β-hydrolase domain containing 6 (ABHD6), were significantly downregulated after sustained morphine exposure.
The downregulation of ABHD6 expression following sustained morphine exposure may be a mechanism underlying opioid-mediated long-term synaptic depression and participate in opioid reward. Interestingly, our qPCR result showed that the expression of ABHD6 was not altered at the mRNA level, suggesting its downregulation detected by the proteomics is not at the transcription level. CB2R is a critical member of the endogenous cannabinoid system but is barely detected by current mass spectrometry-based techniques due to its low expression level (Marchalant et al., 2014). Our qRT-PCR experiments found that CB2R was significantly decreased by repeated morphine treatment. This downregulation of CB2R may be involved in a regulatory process of sustained morphine in the facilitation of the rewarding behavior (Xi et al., 2011; Navarrete et al., 2013; Ortega-Álvaro et al., 2015; Grenald et al., 2017). Overall, these studies suggest that sustained opioids exert regulatory effects on the VTA endogenous cannabinoid system.
The endogenous cannabinoid and opioid systems are two critical neuromodulatory systems, which share similar pharmacological features, including the downstream signaling of µ-opioid receptors (MORs) and CB1Rs and behavioral outcomes (analgesia, sedation and reward) (Wenzel and Cheer, 2018). Recent evidence shows that these two systems are functionally interacted in the modulation of reward and addiction. Δ9-Tetrahydrocannabinol (THC)-induced CPP is eliminated in MOR-knockout mice (Ghozland et al., 2002) and THC self-administration is attenuated by opioid receptor antagonist naloxone (Braida et al., 2001; Justinova et al., 2004). Reciprocally, genetic depletion of CB1Rs or the application of CB1R antagonist rimonabant blocks opioid-induced CPP and self-administration (Ledent et al., 1999; Martin et al., 2000; Cossu et al., 2001; Navarro et al., 2001; Navarro et al., 2004; Caillé and Parsons, 2006). Currently, the underlying mechanisms of the functional interactions between the two systems remains to be elucidated, but the interactions between MOR and CB1R may be an explanation (Wenzel and Cheer, 2018).
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