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Review
. 2022 Aug 5:16:932546.
doi: 10.3389/fnsys.2022.932546. eCollection 2022.

The role of enkephalinergic systems in substance use disorders

Lauren G Rysztak  1   2 , Emily M Jutkiewicz  1
Affiliations
Review

The role of enkephalinergic systems in substance use disorders

Lauren G Rysztak et al. Front Syst Neurosci. .

Abstract

Enkephalin, an endogenous opioid peptide, is highly expressed in the reward pathway and may modulate neurotransmission to regulate reward-related behaviors, such as drug-taking and drug-seeking behaviors. Drugs of abuse also directly increase enkephalin in this pathway, yet it is unknown whether or not changes in the enkephalinergic system after drug administration mediate any specific behaviors. The use of animal models of substance use disorders (SUDs) concurrently with pharmacological, genetic, and molecular tools has allowed researchers to directly investigate the role of enkephalin in promoting these behaviors. In this review, we explore neurochemical mechanisms by which enkephalin levels and enkephalin-mediated signaling are altered by drug administration and interrogate the contribution of enkephalin systems to SUDs. Studies manipulating the receptors that enkephalin _targets (e.g., mu and delta opioid receptors mainly) implicate the endogenous opioid peptide in drug-induced neuroadaptations and reward-related behaviors; however, further studies will need to confirm the role of enkephalin directly. Overall, these findings suggest that the enkephalinergic system is involved in multiple aspects of SUDs, such as the primary reinforcing properties of drugs, conditioned reinforcing effects, and sensitization. The idea of dopaminergic-opioidergic interactions in these behaviors remains relatively novel and warrants further research. Continuing work to elucidate the role of enkephalin in mediating neurotransmission in reward circuitry driving behaviors related to SUDs remains crucial.

Keywords: circuitry; enkephalin; opioid; reward; substance use disorder.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Brain regions and pathways implicated in enkephalin-mediated reward-related behaviors. Dopamine neurons in the VTA that project to the NAc are modified by MORs on GABAergic interneurons. Activation of MORs and DORs, likely by enkephalins, within the NAc modulate dopamine, GABA, glutamate, and acetylcholine release. D2 MSNs express enkephalin and project to the VP and are believed to be a crucial circuit for reinstatement behaviors. Figure created using Biorender.com. NAc, nucleus accumbens; GP, globus pallidus; VP, ventral pallidum; VTA, ventral tegmental area; MOR, mu opioid receptor; DOR, delta opioid receptor; MSNs, medium spiny neurons.
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