Abstract
Rationale
Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists.
Objectives
We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018).
Methods
Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032–0.1 mg/kg) and salvinorin A (0.00032–0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.01–0.32 mg/kg); the MOR agonist, oxycodone (0.0032–0.32 mg/kg); and as controls, cocaine (0.032–0.32 mg/kg) and ketamine (0.32–10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10–320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration.
Results
Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture.
Conclusions
Atypical “biased” KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.
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Funding
This research was supported by National Institute on Drug Abuse or National Institute on Alcohol Abuse and Alcoholism grants DA039167 to K.B.F., DA018151 to T.E.P., AA016179 to D.M.P., and DA045011 to S.L.H. The authors would like to thank Josh Woods, Kandace Farmer, Jessica Howard, Jemma Cook, Lais Berro, Yvonne Zuchowski, Tanya Pareek, and John Overton for their technical assistance. Morgan Brasfield is now at William Carey University in Hattiesburg, MS 39401.
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All procedures were approved by the University of Mississippi Medical Center’s Institutional 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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Huskinson, S.L., Platt, D.M., Brasfield, M. et al. Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys. Psychopharmacology 237, 2075–2087 (2020). https://doi.org/10.1007/s00213-020-05519-7
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DOI: https://doi.org/10.1007/s00213-020-05519-7