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.

Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

“…Although repeated exposure to cocaine produces enduring increases in synaptic strength in both NAc shell and core, we recently demonstrated NAc synaptic plasticity following repeated amphetamine (22,24,(32)(33)(34), which raises a question of whether cocaine, rather than morphine, may be unusual in regards to plasticity in the NAc core. That said, given that the behavioral and neurochemical effects of opiates are dependent on activation of mu opioid receptors (2,35), the regional differences in morphine-induced plasticity demonstrated here may be related to the higher prevalence of mu opioid receptors in the NAc shell compared with the core (36,37).…”

“…However, side effects such as euphoria and the development of tolerance and dependence contribute to an increasing diversion of these readily available compounds for nontherapeutic use (2). Opioid agonist-based treatments are known to reduce some aspects of opioid addiction.…”

“…Opioid agonist-based treatments are known to reduce some aspects of opioid addiction. On the other hand, these therapies often lead to high relapse rates when discontinued because they fail to eliminate key aspects of addiction such as conditioned associations that can trigger intense drug craving (2). Currently, development of alternative treatments for opioid addiction is hampered by a distinct lack of knowledge of the cellular plasticity that underlies persistent opioid-induced changes in behavior.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Opioids and long-term depression. The NAc is rich with opioid neuropeptides and receptors expressed both pre-and postsynaptically (Mansour et al, 1988(Mansour et al, , 1995McGinty, 2007;Chartoff and Connery, 2014). Unfortunately, despite the fact that heroin acts on m-opioid receptors, not much is known about the role of opioids in modulating glutamate neurotransmission in the NAc.…”

Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal

“…We discovered that this effect was still present after a 2-month withdrawal period and was therefore very long lasting and possibly even permanent. Increased pNR1 could play a role in other long-term effects of chronic morphine exposure and Phospho-NR1 Increases in Acute and Extended Morphine Withdrawal subsequent withdrawal such as increased excitatory postsynaptic current inactivation rates (Martin et al, 1999), alterations in dendritic spines (Robinson and Kolb, 1999), craving, or relapse (Chartoff and Connery, 2014).…”