RT Journal Article
SR Electronic
T1 Effects of Kappa Opioid Receptor Agonists on Fentanyl vs. Food Choice in Male and Female Rats: Contingent vs. Non-Contingent Administration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.28.225060
DO 10.1101/2020.07.28.225060
A1 E. Andrew Townsend
YR 2020
UL http://biorxiv.org/content/early/2020/07/29/2020.07.28.225060.abstract
AB 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-versus-food choice were compared under conditions where the KOR agonists were added to the self-administered fentanyl (contingent delivery) or administered as pretreatments (non-contingent delivery) in male and female rats. The effects of increasing and decreasing the magnitude of the alternative food reinforcer were also determined.Methods Rats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 μg/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 mg/kg) and nalfurafine (3.2-32 μg/kg) were administered as acute pretreatments (non-contingent administration). nor-BNI (32 mg/kg) was administered prior to contingent and non-contingent KOR-agonist treatment in Experiment 3. Experiment 4 evaluated the effects of increasing and decreasing the magnitude of the non-drug reinforcer.Results Both U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. Non-contingent U50488 and nalfurafine administration decreased rates of fentanyl and food self-administration without altering fentanyl choice. Both contingent and non-contingent U50488 and nalfurafine effects on fentanyl choice were attenuated by nor-BNI. Fentanyl choice was sensitive to increases and decreases in the magnitude of the non-drug reinforcer.Conclusions These results demonstrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.Competing Interest StatementThe authors have declared no competing interest.