It's MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system

Abstract

Opioids selective for the G protein-coupled mu opioid receptor (MOR) produce potent analgesia and euphoria. Heroin, a synthetic opioid, is considered one of the most addictive substances, and the recent exponential rise in opioid addiction and overdose deaths has made treatment development a national public health priority. Existing medications (methadone, buprenorphine, and naltrexone), when combined with psychosocial therapies, have proven efficacy in reducing aspects of opioid addiction. Unfortunately, these medications have critical limitations including those associated with opioid agonist therapies (e.g., sustained physiological dependence and opioid withdrawal leading to high relapse rates upon discontinuation), non-adherence to daily dosing, and non-renewal of monthly injection with extended-release naltrexone. Furthermore, current medications fail to ameliorate key aspects of addiction such as powerful conditioned associations that trigger relapse (e.g., cues, stress, the drug itself). Thus, there is a need for developing novel treatments that target neural processes corrupted with chronic opioid use. This requires a basic understanding of molecular and cellular mechanisms underlying effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. The focus of this review is to discuss how crosstalk between MOR-associated G protein signaling and glutamatergic neurotransmission leads to immediate and long-term effects on emotional states (e.g., euphoria, depression) and motivated behavior (e.g., drug-seeking, relapse). Our goal is to integrate findings on how opioids modulate synaptic release of glutamate and postsynaptic transmission via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in the nucleus accumbens and ventral tegmental area with the clinical (neurobehavioral) progression of opioid dependence, as well as to identify gaps in knowledge that can be addressed in future studies.

Keywords: AMPA; GluR1; NMDA; heroin; morphine; opioid withdrawal syndrome; plasticity.

FIGURE 1

Interactions between MOR and glutamatergic neurotransmission in the nucleus accumbens (NAc). MORs are coupled to inhibitory G_αi proteins and are found on glutamatergic and GABAergic terminals and postsynaptically on (primarily) D1 receptor-expressing MSNs. Acute opioids: Acute MOR activation in a naïve animal suppresses GABA and glutamate release via inhibition of Ca²⁺ and activation of K⁺ conductances, as well as inhibition of cAMP-mediated activation of non-selective cation pacemaker currents (I_h). Postsynaptic NMDAR currents are augmented via MOR-induced PKC activation. There is no known data on the acute, immediate effects of opioids on AMPAR expression/localization/function in naïve animals. Chronic opioids: Inhibitory effect of presynaptic mGluR2/3 receptors to inhibit glutamate release is increased during chronic opioid treatment. Surface expression of GluR1 subunits is decreased on MSNs, with no change in total AMPAR subunit expression. Levels and/or function of the NR2A NMDAR subunit are increased, which may contribute to a decreased affinity for the co-agonist glycine and a decreased sensitivity to PKC-mediated NMDAR activation. Opioid withdrawal: Extracellular glutamate levels are increased, but synaptic transmission may be reduced via enhanced mGluR2/3 autoreceptor function. GABA release is potentiated via augmented cAMP and PKA pathways. NR2B surface expression is increased, perhaps resulting in an increase in silent synapses devoid of AMPARs. Upregulated cAMP and PKA signaling leads to increased P-GluR1^Ser845, which may prime AMPARs containing GluR1 at the plasma membrane to be shuttled to synapse upon CaMKII activation. PfC, prefrontal cortex; VSub, ventral subiculum; BlA, basolateral amygdala; MSN, medium spiny neuron.

FIGURE 2

Interactions between MOR and glutamatergic neurotransmission in the ventral tegmental area (VTA). Acute opioids: Acute MOR activation in a naïve animal inhibits glutamatergic neurons via arachidonic acid-dependent potentiation of voltage-dependent K⁺ channels. GABA neurons are inhibited via G protein-mediated inhibition of Ca²⁺ and activation of K⁺ conductances, and GABA release is decreased via inhibition of cAMP-dependent facilitation of transmitter release. This leads to disinhibition of dopamine neurons and increased somato-dendritic dopamine release. Stimulatory dopamine D5 receptors on dopamine neurons are activated and, in conjunction with CaMKII, facilitate increased surface expression of GluR1 subunits. Chronic opioids: Dopamine firing rate remains elevated. Tolerance to inhibitory effects of MOR activation on GABAergic neurons develops through compensatory upregulation of cAMP systems, but dopamine neuron K⁺ channels are downregulated, enabling increased basal firing rate and burst activity of dopamine neurons. Total and surface GluR1 is increased and NR1 subunits are increased. Opioid withdrawal: Activity of GABA neurons is increased due to disinhibition of Ca²⁺ channels and reduced activation of K⁺ channels. GABA release is increased due to unmasking of upregulated cAMP systems. Extracellular glutamate levels are increased, but inhibitory presynaptic GABA_B and mGluR2/3 receptor function is enhanced, leading to decreased synaptic release of glutamate. RMTG, rostromedial tegmental nucleus; PPTg, pedunculopontine tegmental nucleus, BNST, bed nucleus of the stria terminalis; DA, dopamine.

FIGURE 3

Naloxone-precipitated morphine withdrawal increases GluR1 phosphorylation in a PKA-dependent manner. (A) Rats were subcutaneously implanted with morphine (2 × 75 mg) or placebo pellets and returned to their home cages for 3 days in order for morphine dependence to develop. Naloxone (0.0, 0.01, or 1.0 mg/kg, SC) was injected and rats killed 30 min later. Brains were removed and frozen, 1-mm³ punches of the NAc were extracted, and P-GluR1^Ser845 and β-actin (protein loading control) were quantified on immunoblots. Data are expressed as fold-induction of P-GluR1/actin levels relative to non-dependent (placebo) rats treated with vehicle. *p < 0.05, **p < 0.01 compared to non-dependent (placebo) rats treated with vehicle. ∧p < 0.05 comparing groups under bar. N = 5–9 rats/group. Modified from Chartoff et al. (2006). (B) PKA is required for super-induction of P-GluR1^Ser845 during naloxone-precipitated morphine withdrawal. Primary striatal cultures were treated chronically with either vehicle or morphine (morph, 10 μM) for 6 days, followed by a 1.5-h treatment with vehicle [dimethylsulfoxide (DMSO)] or the PKA inhibitor H89 (20 μM), followed by a 30-min incubation with vehicle or naloxone (nal, 10 μM), and the dopamine D1 receptor agonist SKF 82958 (SKF, 50 μM) for 15 min. The ratio of P-GluR1^Ser845/actin was determined for each sample and normalized to the control group ratio to yield a fold induction. Data are plotted as the mean fold induction ± SEM. *p < 0.05, **p < 0.01 compared with control. ∧p < 0.05, ∧∧p < 0.01 comparing groups designated by solid lines. N = 3 experiments with treatments in triplicate (see Chartoff et al., 2003a for details).