Yasamin Yazdani

Background: The opioid crisis has been a challenging one to tackle, and deaths from opioid overdose continue to rise.¹ Addiction to opioids is centered around firing of dopaminergic (D1/D2) medium spiny neurons (MSNs) in the nucleus accumbens (NAc) after opioid firing of Mu opioid receptors (MORs). ⁴ Patients recovering from opioid use disorder usually receive a maintenance opioid agonist such as methadone to prevent relapse or abuse of opioids.³ Research shows that there are drug-specific responses of D1-MSNs involved in influencing reward-seeking behavior, suggesting that targeting these MSNs could be an alternative therapeutic route for opioid use disorder.

Objective: In this review, we will discuss the significance of D1-MSNs in triggering reward-seeking behaviors in opioid use disorder, their mechanisms, and subsequent outcomes.

Search Methods: This review was written after an online search for review and primary research articles published between 2017 and 2023 from the PubMed database using the keywords: “opioid use disorder”, “nucleus accumbens”, and “dopaminergic medium spiny neurons”.

Results: While not an opioid, studies indicated that stimulation of the NAc with cocaine increased activity of MSNs with both D1 and D2 receptors, suggesting their involvement in the reward neurocircuitry.⁶  Furthermore, morphine stimulation of MSNs with dopaminergic receptors triggered reduced expression of D2-MSNs.⁷ This finding suggests that opioids are cell- and receptor- specific.⁷ Not only are addictive substances receptor-specific, but the subsequent targets of MSNs are tailored to the subset of dopaminergic receptors targeted. ⁸ While not an opioid, cocaine stimulus of NAc MSNs showed that D1+MSNs projected to the ventral tegmental area (VTA) and ventral pallidum (VP) of the brain, while D1- (D2) MSNs projected to the VP only.⁸ Additionally, studies involving mice showed that when drug extinction training was taught to mice conditioned to cocaine, drug-context exposure increased D2-MSN expression while mice who were made to stop cocaine immediately showed an increase in D1-MSN expression following drug-context exposure, suggesting that these neuronal receptor types are responsible for specific outcomes of addiction.⁹ Finally, a study with fentanyl showed that abstinence from the drug resulted in reduced dendritic complexity on D1-MSNs, and led to negative affective behavior in mice, suggesting that that D1-MSNs induce drug-seeking behavior.¹⁰

Conclusion: These studies have shown the significance of DA-MSNs in the reward neurocircuitry of opioid use disorder; specifically, D1-MSN firing is linked to drug-seeking behaviors. By focusing on alleviating the drug-seeking side effects of drug-abstinence using D1-MSNs as a target, new therapies for opioid or fentanyl use disorder could follow.

Works Cited:

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