Systemic Effects of AT‐121 as a Safe Analgesic without Abuse Liability in Primates

Abstract

AT‐121 is a newly developed bifunctional nociceptin/orphanin FQ peptide (NOP)/mu opioid peptide (MOP) receptor agonist that displays full efficacy on NOP receptors and partial efficacy on MOP receptors. The aim of this study was to establish the functional profile of AT‐121 as an analgesic by using several behavioral and physiological assays in rhesus monkeys (Macaca mutatta). Systemic administration of AT‐121 (0.003–0.03 mg/kg) dose‐dependently produced antinociceptive and antihypersensitive effects. Both NOP receptor antagonist J‐113397 (0.1 mg/kg) and MOP receptor antagonist naltrexone (0.03 mg/kg) equally attenuated AT‐121‐induced antinociception. These antagonist studies demonstrate that both NOP and MOP receptor components contribute to the antinociceptive effects exhibited by AT‐121 in primates. More importantly, a full antinociceptive dose (0.03 mg/kg) and a dose 10‐fold higher (0.3 mg/kg) of AT‐121 did not affect physiological functions including respiration, cardiovascular activities, and body temperature as measured by the telemetry probes (DSI, model D70‐PCTR). These findings indicate a wider therapeutic window afforded by AT‐121 as compared to MOP receptor agonists. In addition, AT‐121 did not produce reinforcing effects in monkeys under the progressive‐ratio schedule of drug self‐administration. Following repeated administration of AT‐121, monkeys did not show physiological withdrawal signs precipitated by both NOP and MOP receptor antagonists. Taken together, these translational nonhuman primate studies demonstrate that AT‐121 is an effective and safe analgesic without typical opioid‐associated side effects. Lack of reinforcing effects and acute physical dependence by AT‐121 strongly supports the therapeutic potential of selected bifunctional NOP/MOP agonists as innovative analgesics in humans.Support or Funding InformationSupported by the US‐PHS grants DA‐032568 and DA‐035359 and the US‐DOD grant W81XWH‐13‐2‐0045.