Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys

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.