Effects of kappa opioid receptor agonists on fentanyl vs. food choice in male and female rats: contingent vs. non-contingent administration

Abstract

Rationale Strategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists. Objectives The effects of KOR agonists (U50488, nalfurafine) on fentanyl-vs.-food choice were compared under conditions where the KOR agonists were added to the intravenously self-administered fentanyl (contingent delivery) or administered as subcutaneous pretreatments (non-contingent delivery) in male and female rats. Methods Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32–10\xa0μg/kg/infusion) and food reinforcement. In experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In experiment 2, U50488 (1–10\xa0mg/kg) and nalfurafine (3.2–32\xa0μg/kg) were administered as acute pretreatments (non-contingent administration). The selective KOR antagonist, nor-BNI (32\xa0mg/kg), was administered prior to contingent and non-contingent KOR-agonist treatment in experiment 3. Results Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. However, evidence for punishment corresponded with an elimination of operant responding in the majority of rats. Non-contingent U50488 and nalfurafine administration only decreased the number of choices made during the behavioral session without altering fentanyl choice. Contingent and non-contingent KOR-agonist effects on fentanyl choice were both attenuated by nor-BNI. Conclusions These results illustrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.