7.1 Mu opioid receptors (MORs)
MORs are expressed by many neurons involved in regulation of nigrostriatal and mesolimbic dopamine transmission, including GABAergic neurons in the VTA, striatal SPNs that project to the midbrain, striatal CINs, and on glutamatergic afferents to the striatum (Darcq & Kieffer, 2018; Sgroi & Tonini, 2018). Regulation of dopamine transmission is complex and depends on the site of MOR activation. In the midbrain, activation of MOR on local and striatal GABAergic inputs results in disinhibition of dopamine neurons (Cui et al., 2014; Fields & Margolis, 2015; Johnson & North, 1992). In the striatum, MORs can be found in somatodendritic compartments of SPNs and CINs where they impact neuronal excitability (Ponterio et al., 2013). Decreasing CIN firing by activating MORs decreases spontaneous dopamine transients in the NAc (Yorgason et al., 2017). In addition, activation of MORs inhibits excitatory thalamostriatal transmission (Atwood et al., 2014), and this could in turn reduce synchronous activation of CINs and ACh-evoked dopamine release. Concordantly, dopamine transmission is sometimes reduced in the dorsal striatum and NAc following MOR activation as measured by microdialysis or voltammetry, although the nature of MOR modulation of dopamine transmission can vary by striatal subregion (Campos-Jurado et al., 2017; Pentney & Gratton, 1991).
Evidence that MORs are the opioid receptor subtype that is responsible for the euphoric and addictive properties of opioid drugs comes from the finding that MOR knockout mice do not show behavioral signs of reward in response to opioid administration (Matthes et al., 1996). In addition to mediating the rewarding and reinforcing properties of opioid drugs, activation of MORs also contributes to the rewarding properties of non-opioid drugs including alcohol, Δ9-THC, and nicotine (Charbogne et al., 2014; Darcq & Kieffer, 2018). In the case of alcohol use disorder, the MOR antagonist naltrexone is effective for reducing alcohol craving, highlighting the translational importance of this mechanism (Hillemacher et al., 2011). Interestingly, restoring MOR expression in D1-expressing SPNs is sufficient to rescue opioid-induced dopamine release and partially rescues opioid self-administration, likely because MOR-mediated inhibition of striatonigral transmission increases activity of midbrain dopamine neurons (Cui et al., 2014). Because systemic MOR activation with opioid drugs could have differential effects on various drivers of dopamine release (i.e., somatic firing of midbrain dopamine neurons vs. ACh-dependent local mechanisms), it will be interesting to determine how inhibition of local release mechanisms and concurrent disinhibition of dopamine neuron firing contributes to both acute drug responses and transitions to maladaptive opioid-taking behaviors. It is also important to consider that exposure to exogenous opioid drugs can rapidly impair MOR signaling at some synapses (Atwood et al., 2014). Opioid-mediated desensitization could have profound effects on how MORs modulate dopamine transmission in the case of repeated exposures, particularly if different populations of MORs are subject to different degrees of desensitization.