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Roles of MOP and NOP receptors in regulating buprenorphine‐induced physiological responses in monkeys

Buprenorphine is known as a mu opioid receptor (MOP) partial agonist, but its analgesia was attenuated by activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine‐induced physiological responses in monkeys. Systemic buprenorphine (0.01–0.1 mg/kg) dose‐dependently produced antinociception, respiratory depression, and itch/scratching responses. A MOP antagonist, naltrexone 0.03 mg/kg, produced similar degrees of rightward shifts of buprenorphine's dose‐response curves for all three endpoints and confirmed that they were MOP‐mediated effects. In contrast, a NOP antagonist, J‐113397 0.1 mg/kg, did not change buprenorphine‐induced effects, indicating that there were no functional NOP receptors in buprenorphine‐induced actions. More importantly, a NOP agonist Ro 64–6198 enhanced buprenorphine‐induced antinociception, and the dose‐addition analysis revealed that systemic combination of buprenorphine and Ro 64–6198 produced superadditive antinociceptive effects. These findings provided functional evidence that co‐activation of MOP and NOP receptors produced synergistic antinociception in primates. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics (Supported by USPHS grant AR‐059193).