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  • Compared to methadone or morphine buprenorphine is


    Compared to methadone or morphine, buprenorphine is a partial mu-opioid agonist, which shows high affinity for, and slow dissociation from, mu-opioid receptors. This maintenance of homeostasis may help to counter the development of an overt withdrawal syndrome, and may explain the lower risk of development of physical dependence to buprenorphine compared to methadone. Recently, we found that the infusion of either stromal cell-derived growth factor-1alpha (SDF-1α/CXCL12) or gp120 into the brain diminished the acute function of morphine and methadone but did not affect buprenorphine (Benamar et al., 2010, Benamar et al., 2011, Chen et al., 2011, Palma et al., 2011). The present results show that such a finding extends to the chronic effect of buprenorphine, and indicates that gp120 or the neuro-inflammatory response associated with the presence of this viral protein in the PAG did not promote the development of physical dependence to buprenorphine.
    Conflict of interest
    Introduction Monoacylglycerol lipase (MGL) hydrolyzes the endocannabinoid, 2-arachidonoylglycerol (2-AG), to arachidonic 1-NM-PP1 (AA) and glycerol (Blankman and Cravatt, 2013). In the brain, hydrolysis of 2-AG by MGL is the principal source of AA for the production of prostaglandins (PGs) (Nomura et al., 2011). Thus, inhibition of MGL can affect neuronal function by enhancing endocannabinoid signaling (Viader et al., 2015) and decreasing PG-mediated inflammation (Grabner et al., 2016, Nomura et al., 2011). Both of these actions might protect the CNS from excitotoxic insult. Activation of the endocannabinoid system protects neuronal function in animal models of epilepsy, stroke and Alzheimer's disease (Chen et al., 2012, Pacher et al., 2006). Neuroinflammation impairs neuronal function (Heneka et al., 2015), and elevated PG levels contribute to neuronal dysfunction in animal models of status epilepticus (Jiang et al., 2013), pain (Zhao et al., 2007) and Alzheimer's disease (Johansson et al., 2015). Here we examined the effects of MGL inhibition in an in vitro model of a neuroinflammatory disorder using JZL184, a potent and selective inhibitor of MGL (Grabner et al., 2016, Pan et al., 2009). HIV-associated neurocognitive disorder (HAND) afflicts almost half of HIV-infected individuals (Ellis et al., 2007, Saylor et al., 2016). Cognitive decline in HAND correlates closely with synaptodendritic damage such as dendritic pruning and degradation of synaptic proteins (Ellis et al., 2007, Ellis et al., 2009). Because HIV does not infect neurons, HIV neurotoxicity is indirect and thought to be mediated by a neuroinflammatory response to viral proteins and inflammatory cytokines released by infected microglia and macrophages (Ellis et al., 2007, Kaul et al., 2001, Saylor et al., 2016). The HIV envelope protein, gp120, has been detected in the brain tissue of HAND patients (Jones et al., 2000, Nath, 2002), is shed by infected cells (Kaul et al., 2001), and is a potent neurotoxin (Toggas et al., 1994). Synapse loss is the hallmark of HAND and gp120 induces significant loss of synapses in both primary neuronal cultures and transgenic mice (Iskander et al., 2004, Kim et al., 2011, Toggas et al., 1994). When applied to hippocampal cultures composed of microglia, astrocytes and neurons, gp120IIIB binds to CXCR4 on microglia evoking the release of the inflammatory cytokine interleukin-1β (IL-1β) (Kim et al., 2011, Viviani et al., 2006). HIV gp120-induced synapse loss is blocked by an IL-1 receptor antagonist (Kim et al., 2011). Whether modulating endocannabinoid tone affects this process of neuroinflammatory synapse loss is not known. Thus, gp120-induced loss of synapses between hippocampal neurons in culture provides a model to study the potential for inhibition of MGL to protect synaptic function. The present study demonstrates that JZL184 completely protects from gp120-induced synapse loss. The contributions of enhanced endocannabinoid tone and reduced PGE2-mediated neuroinflammation to synapse protection were determined. The dual mechanisms of protection that result from MGL inhibition might be particularly beneficial in neurodegenerative disorders with a strong neuroinflammatory component like HAND.