PT  - JOURNAL ARTICLE
AU  - Colette Cremeans
AU  - Erin Gruley
AU  - Donald Kyle
AU  - Mei-Chuan Ko
TI  - Roles of Mu Opioid Receptors and Nociceptin/Orphanin FQ Peptide Receptors in Buprenorphine-Induced Physiological Responses in Primates
AID  - 10.1124/jpet.112.194308
DP  - 2012 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.112.194308
4099  - http://jpet.aspetjournals.org/content/early/2012/06/28/jpet.112.194308.short
4100  - http://jpet.aspetjournals.org/content/early/2012/06/28/jpet.112.194308.full
AB  - Buprenorphine is known as a mu opioid peptide (MOP) receptor agonist, but its antinociception was compromised 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 primates. Effects of MOP antagonist (naltrexone), NOP antagonist (J-113397), and NOP agonists (Ro 64-6198 and SCH 221510) on buprenorphine were studied in three functional assays for measuring analgesia, respiratory depression, and itch in primates. Over the dose range of 0.01-0.1 mg/kg, buprenorphine dose-dependently produced antinociception, respiratory depression, and itch/scratching responses, and there was a ceiling effect at higher doses, 0.1-1 mg/kg. Naltrexone 0.03 mg/kg produced similar degrees of rightward shifts of buprenorphine's dose-response curves for all three endpoints. Mean pKB values of naltrexone, 8.1-8.3, confirmed that MOP receptors mainly mediated buprenorphine-induced antinociception, respiratory depression, and itch/scratching. In contrast, J-113397 0.1 mg/kg did not change buprenorphine-induced physiological responses, indicating that there were no functional NOP receptors in buprenorphine-induced effects. More importantly, both NOP agonists, Ro 64-6198 and SCH 221510, enhanced buprenorphine-induced antinociception without respiratory depression and itch/scratching. The dose-addition analysis revealed that buprenorphine in combination with the NOP agonist synergistically produced antinociceptive effects. These findings provided functional evidence that activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, co-activation of MOP and NOP receptors produced synergistic antinociception without other side effects. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics.