Effects of Kappa Opioid Receptor Agonists on Fentanyl vs. Food Choice in Male and Female Rats: Contingent vs. Non-Contingent Administration

Abstract

RationaleStrategies 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.ObjectivesThe 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.MethodsRats 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.ResultsBoth 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.ConclusionsThese results demonstrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.

Insights into the mechanisms underlying opioid use disorder and potential treatment strategies

“…A series of studies showed that acute nalfurafine dose‐dependently suppresses morphine‐induced hyperlocomotion and that repeated nalfurafine treatment not only blocks naloxone‐precipitated withdrawal syndromes after chronic morphine treatment but also reduces morphine‐induced conditioned place preference as well as oxycodone‐induced conditioned place preference and self‐administration in rodents by activating κ receptor(Kaski et al, 2019; Tsuji et al, 2000; Zamarripa, Patel, et al, 2020; Y. Zhang & Kreek, 2020). However, under a drug‐versus‐food choice procedure, non‐contingent U50488 and nalfurafine administration decreases the number of choices made during the behavioural session without altering fentanyl choice in rats (Townsend, 2021),. This suggests that κ receptor agonists may decrease operant behaviours by non‐selectively decreasing behavioural responses through impairing sensory, cognitive or motor functions (undesired effects), rather than decreasing sensitivity to the reinforcing effects of the self‐administered opioid (the desired effect).…”

“…This suggests that κ receptor agonists may decrease operant behaviours by non‐selectively decreasing behavioural responses through impairing sensory, cognitive or motor functions (undesired effects), rather than decreasing sensitivity to the reinforcing effects of the self‐administered opioid (the desired effect). Although κ receptor agonists can function as punishers, decrease opioid self‐administration and choice when mixed and co‐administered with the abuse drug (Townsend, 2021; Zamarripa, Naylor, et al, 2020), it is unlikely that the abuse liability of the drugs of abuse can be eliminated by mixing it with another drug. Overall, this body of literature does not support the clinical utility of κ receptor agonists as potential treatment strategies for opioid use disorder.…”

Evaluation of Antinociceptive Effects of Chitosan-Coated Liposomes Entrapping the Selective Kappa Opioid Receptor Agonist U50,488 in Mice

“…The trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide derivative U-50,488 is a selective KOR agonist, possessing analgesic, cough suppressant, and diuretic properties. It also suppresses the psychostimulant reward through the inhibition of dopamine signaling in the addiction pathways [ 10 , 11 , 12 ], with obvious influence in decreasing amphetamine-induced psychomotor disturbances [ 13 ], in preventing cocaine [ 14 ] or nicotine-induced motor troubles [ 15 ], and in reducing the charges of morphine [ 16 ] or fentanyl [ 17 ] self-administration in rodents. Other research has evidenced the beneficial effects of U50,488 on L-dopa attenuation of motor dyskinesia in rodents and primates with experimental-induced Parkinsonian manifestations [ 18 , 19 ].…”