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.

List of Abbreviations: conditioned place preference (CPP); delta-opioid (DOPr); ethylketocyclazocine (EKC); Food and Drug Administration (FDA); kappa-opioid receptors (KOPr); mu-opioid receptor (MOPr); nociceptin receptor (NOPr); percentage of maximum possible effect (% MPE); Warm Water Tail Withdrawal (WWTW).

Substance use disorders (SUDs) – the overuse and dependence on at least one substance – have a lifetime prevalence of ~10% in the U.S. While buprenorphine (BUP) treatment reduces relapse rates, it is only marginally effective, as 70% of SUD patients relapse within a year. Due to BUP’s marginal effectiveness and abuse potential, there is a need to improve SUD therapies that prevent relapse to multiple drugs of abuse after exposure to stress, drug‐associated context and drug priming. Here we evaluate BUP and two analogs for their ability to inhibit cocaine‐ and stress‐induced relapse using a conditioned place preference (CPP) paradigm. Pharmacologically, BUP is a potent (sub nM) partial agonist at the m‐opioid receptor (MOR) with potent antagonist activity at the k‐(KOR), and d‐opioid receptors (DOR). In vitro BUP can act as a weak (mM) partial agonist at the nociceptin/OrphaninFQ (NOP) receptor with uncertain in vivo consequences. We measured in vitro potency and efficacy using [35S]GTPgS functional assays in CHO cells separately expressing DOR, KOR, MOR or NOP. Since NOP receptor agonists reduce relapse in animal models, we compared BU10119 with NOP agonist activity (EC50 = 120 nM ± 20; EMAX = 44% ± 5%) or BU12004 with NOP antagonist activity (KB = 190 nM ±30) to BUP (EC50 = 1300 nM ± 320; EMAX = 39% ± 7%). Furthermore, BU12004 and BU10119 were MOR antagonists (KB = 0.42 nM ± 0.08 and KB = 1.1 nM ± 0.2, respectively) with less abuse liability than the MOR partial agonist BUP (EC50 = 0.79 nM ± 0.31; EMAX = 34% ± 6%). BUP, BU10119, and BU12004 were all potent antagonists at DOR and KOR. BU10119 (1.0 mg/kg) attenuated cocaine‐primed reinstatement in CPP, but 10 mg/kg BU12004 did not. BUP trended toward reduced drug‐primed reinstatement. The in vivo rank order of BU10119 >BUP >BU12004 matches the rank order for NOP agonism in vitro. Additionally, 1.0 mg/kg of either BU10119 or BU12004 blocked swim stress‐primed reinstatement, ostensibly due to their KOR antagonist activity. Taken together, BU10119 provides a promising lead to treat SUDs with better effectiveness and reduced abuse potential compared to BUP. Support or Funding Information Supported by NIDA R01 DA07315 and 035316.