PPL-138 (BU10038): A bifunctional NOP/mu partial agonist that reduces cocaine self-administration in rats

Neuropharmacology. 2022 Jun 15:211:109045. doi: 10.1016/j.neuropharm.2022.109045. Epub 2022 Apr 1.

Abstract

The search for new and effective treatments for cocaine use disorder (CUD) is a priority. We determined whether PPL-138 (BU10038), a compound with partial agonist activity at both nociceptin opioid peptide (NOP) and mu-opioid receptors, reduces cocaine consumption, reinstatement, and whether the compound itself produces reinforcing effects in rats. Using an intermittent access (IntA) cocaine self-administration procedure, we found that PPL-138 (0.1 and 0.3 mg/kg) effectively decreased the total number of cocaine infusions and burst-like cocaine intake in both male and female rats. Responses for food in an IntA model of food self-administration were not altered for either sex, although locomotor activity was increased in female but not male rats. Blockade of NOP receptors with the selective antagonist J-113397 (5 mg/kg) did not prevent the PPL-138-induced suppression of cocaine self-administration, whereas blockade of mu-opioid receptors by naltrexone (1 mg/kg) reversed such effect. Consistently, treatment with morphine (1, 3, and 10 mg/kg) dose-dependently reduced IntA cocaine self-administration measures. PPL-138 also reduced reinstatement of cocaine seeking at all doses examined. Although an initial treatment with PPL-138 (2.5, 10, and 40 μg/kg/infusion) appeared rewarding, the compound did not maintain self-administration behavior. Animals treated with PPL-138 showed initial suppression of cocaine self-administration, which was eliminated following repeated daily dosing. However, suppression of cocaine self-administration was retained when subsequent PPL-138 treatments were administered 48 h apart. These findings demonstrate that the approach of combining partial NOP/mu-opioid activation successfully reduces cocaine use, but properties of PPL-138 seem to depend on the timing of drug administration.

Keywords: BU10038; Cocaine; Intermittent access; NOP; Opioid; Self-administration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cocaine* / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Isoquinolines
  • Male
  • Naltrexone / analogs & derivatives
  • Nociceptin
  • Opioid Peptides
  • Phenylpropionates
  • Rats
  • Receptors, Opioid / agonists
  • Receptors, Opioid, mu / agonists
  • Self Administration

Substances

  • BU10038
  • Isoquinolines
  • Opioid Peptides
  • Phenylpropionates
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • Naltrexone
  • Cocaine