µ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges.

Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors (MOR) localized to the central nervous system (CNS). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin (5-HT) is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT2A receptor (5-HT 2A R) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HT2AR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HT2AR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HT2AR agonists and/or 5-HT2AR positive allosteric modulators may provide a new pathway for 5-HT2AR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HT2AR agonists as therapeutics for OUD.

Eating driven by the gustatory insula: contrasting regulation by infralimbic vs. prelimbic cortices.

Subregions within insular cortex and medial prefrontal cortex (mPFC) have been implicated in eating disorders; however, the way these brain regions interact to produce dysfunctional eating is poorly understood. The present study explored how two mPFC subregions, the infralimbic (IL) and prelimbic (PRL) cortices, regulate sucrose hyperphagia elicited specifically by a neurochemical manipulation of the agranular/dysgranular region of gustatory insula (AI/DI). Using intra-AI/DI infusion of the mu-opioid receptor (µ-OR) agonist, DAMGO (1 µg), sucrose hyperphagia was generated in ad-libitum-maintained rats, while in the same rat, either the IL or prelimbic (PRL) subregion of mPFC was inactivated bilaterally with muscimol (30 ng). Intra-IL muscimol markedly potentiated AI/DI DAMGO-induced sucrose hyperphagia by increasing eating bout duration and food consumption per bout. In contrast, PRL attenuated intra-AI/DI DAMGO-driven sucrose intake and feeding duration and eliminated the small DAMGO-induced increase in feeding bout initiation. Intra-IL or -PRL muscimol alone (i.e., without intra-AI/DI DAMGO) did not alter feeding behavior, but slightly reduced exploratory-like rearing in both mPFC subregions. These results reveal anatomical heterogeneity in mPFC regulation of the intense feeding-motivational state engendered by µ-OR signaling in the gustatory insula: IL significantly curtails consummatory activity, while PRL modestly contributes to feeding initiation. Results are discussed with regard to potential circuit-based mechanisms that may underlie the observed results.

Dissociable control of µ-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex.

This study explored potentially dissociable functions of mu-opioid receptor (µ-OR) signaling across different cortical territories in the control of anticipatory activity directed toward palatable food, consumption, and impulsive food-seeking behavior in male rats. The µ-OR agonist, DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), was infused into infralimbic cortex (ILC), prelimbic cortex (PrL), medial and lateral ventral orbitofrontal cortices (VMO, VLO), and agranular/dysgranular insular (AI/DI) cortex of rats. Intra-ILC DAMGO markedly enhanced contact with a see-through screen behind which sucrose pellets were sequestered; in addition, rats having received intra-ILC and intra-VMO DAMGO exhibited locomotor hyperactivity while the screen was in place. Upon screen removal, intra-ILC and -VMO-treated rats emitted numerous, brief sucrose-intake bouts (yielding increased overall intake) interspersed with significant hyperactivity. In contrast, intra-AI/DI-treated rats consumed large amounts of sucrose in long, uninterrupted bouts with no anticipatory hyperactivity pre-screen removal. Intra-PrL and intra-VLO DAMGO altered neither pre-screen behavior nor sucrose intake. Finally, all rats were tested in a sucrose-reinforced differential reinforcement of low rates (DRL) task, which assesses the ability to advantageously withhold premature responses. DAMGO affected (impaired) DRL performance when infused into ILC only. These site-based dissociations reveal differential control of µ-OR-modulated appetitive/approach vs. consummatory behaviors by ventromedial/orbitofrontal and insular networks, respectively, and suggest a unique role of ILC µ-ORs in modulating inhibitory control.