Effects of the μ-opioid peptide and nociceptin/orphanin FQ peptide receptor agonist BU08028 on cocaine self-administration in male rhesus monkeys

Cocaine use disorder (CUD) persists as a major public health concern. The lack of US Food and Drug Administration–approved pharmacotherapies for CUD underscores the critical need for developing novel pharmacological treatments. Evidence from rodent models indicates that stimulating brain receptors for the nociceptin/orphanin FQ peptide can decrease self-administration of abused drugs, including cocaine. In the present study, effects of the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxy morphinan- 7-yl]-3,3-dimethylpentan-2-ol (BU08028), an agonist at both μ-opioid peptide and NOP receptors, were characterized in a nonhuman primate model of CUD. Ten male rhesus monkeys responded under a multiple schedule consisting of a fixed-ratio 5 schedule of food pellet delivery followed by a fixed-ratio 30 schedule of intravenous injections of cocaine (0.003–0.1 mg/kg) on a separate manipulandum. After characterizing the effects of acutely administered BU08028 (0.003–0.17 mg/kg, i.v; n = 8), the drug was administered chronically in 4 monkeys using a translational model of pharmacotherapy evaluation. BU08028 was studied during self-administration of a lower (0.01 mg/kg per injection) and a higher (0.1 mg/kg per injection) cocaine dose. BU08028 acutely enhanced the reinforcing effects of cocaine in most monkeys. However, when given chronically, BU08028 decreased the reinforcing effects of the low cocaine dose for several weeks without the development of tolerance, almost no hypersalivation and only transient decreases in food-maintained responding. Self-administration of the higher cocaine dose was unaffected. These data support the development of bifunctional agonists as novel pharmacotherapies for less severe forms of CUD. Significance Statement: Drugs that stimulate μ-opioid peptide and nociceptin/orphanin FQ peptide receptors have shown promise as cocaine use disorder pharmacotherapies in rodent models. In monkeys, chronic treatment with BU08028 decreased cocaine reinforcement in most subjects.