The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.

Mu-opioid agonists (e.g., oxycodone) are highly effective therapeutics for pain. However, they also produce reinforcing effects that increase their likelihood of abuse. Recent strategies in drug development have focused on opioids with biased receptor-signaling profiles that favor activation of specific intracellular pathways over others with the aim of increasing therapeutic selectivity. TRV130, a mu agonist biased towards G-protein signaling, produces antinociceptive effects comparable to the mu agonist, morphine, but exhibits reduced side effects. However, in terms of abuse potential, we know of no published preclinical data investigating the effects of TRV130 as a reinforcer. In the present study, we assessed the relative reinforcing effects of TRV130 and oxycodone, a commonly-prescribed mu agonist, in rats self-administering the drugs under a progressive-ratio (PR) schedule of reinforcement. In addition, we assessed the relative potency and efficacy of TRV130 and oxycodone in rats in a test of thermal antinociception (Hot Plate). For self-administration, male Sprague-Dawley rats (n = 7) self-administered intravenous infusions of TRV130 or oxycodone (0.01-0.32 mg/kg/inj) under a PR schedule of reinforcement. For the Hot-Plate test, male rats (n = 7) received subcutaneous injections of TRV130 (0.1-3.2 mg/kg/inj) or oxycodone (0.1-5.6 mg/kg/inj), and nociceptive response latencies were measured. TRV130 and oxycodone were equi-potent and equi-effective in self-administration and thermal antinociception. This study demonstrates that TRV130 produces reinforcing and antinociceptive effects that are quantitatively similar to oxycodone, and that a biased-signaling profile does not necessarily reduce abuse potential.

Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats.

RATIONALE: Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. OBJECTIVES: The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. METHODS: To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 µg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 µg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. RESULTS: Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. CONCLUSIONS: These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.