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.