Abstract
Rationale
Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement.
Methods
In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine’s effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.).
Results
All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI.
Conclusions
These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine’s punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.
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Acknowledgments
The authors would like to thank Josh Woods, Kandace Farmer, Jessica Howard, Jacob Smith, and Talal Ahmed for their technical assistance.
Funding
This research was supported by the National Institute on Drug Abuse grants DA039167 to K.B.F., DA018151 to T.E.P., DA045011 to S.L.H., and DA048586 to C.A.Z.
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All animal use procedures were approved by the University of Mississippi Medical Center’s Animal Care and Use Committee and were conducted in accordance with the National Research Council’s Guide for Care and Use of Laboratory Animals (8th edition 2011).
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Zamarripa, C.A., Naylor, J.E., Huskinson, S.L. et al. Kappa opioid agonists reduce oxycodone self-administration in male rhesus monkeys. Psychopharmacology 237, 1471–1480 (2020). https://doi.org/10.1007/s00213-020-05473-4
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DOI: https://doi.org/10.1007/s00213-020-05473-4