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Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys

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Abstract

Rationale

Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects.

Objective

The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A.

Methods

Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1–3.2 µg/kg/injection), nalfurafine (0.0032–0.1 µg/kg/injection), triazole 1.1 (3.2–100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components.

Results

Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed.

Conclusions

These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

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Acknowledgements

The authors would like to thank Josh Woods, Jessica Howard, Zachary Smith, Kandace Farmer, and Kristen Dunaway for their technical assistance. The authors would also like to thank Drs. Steve Negus and Matthew Banks for consultation on the programming code used for the choice procedure.

Funding

This research and manuscript preparation were supported by National Institute on Drug Abuse grants DA039167 to K.B.F., DA048586 to C.A.Z., DA018151 to T.E.P., DA045011 to S.L.H, and DA043204 to J.K.R.

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Authors and Affiliations

  1. Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, 39216, USA

    C. Austin Zamarripa, Sally L. Huskinson, James K. Rowlett & Kevin B. Freeman

  2. Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA

    Sally L. Huskinson, James K. Rowlett & Kevin B. Freeman

  3. Center for Innovation and Discovery in Addictions, University of Mississippi Medical Center, Jackson, MS, 39216, USA

    Sally L. Huskinson, James K. Rowlett & Kevin B. Freeman

  4. Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, North Bethesda, MD, 20852, USA

    E. Andrew Townsend

  5. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536, USA

    Thomas E. Prisinzano

  6. Research Triangle Park, Durham, NC, 27709, USA

    Bruce E. Blough

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Zamarripa, C.A., Huskinson, S.L., Townsend, E.A. et al. Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys. Psychopharmacology 241, 305–314 (2024). https://doi.org/10.1007/s00213-023-06486-5

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