title: Roles of μ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates.
abstract: Buprenorphine is known as a μ-opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the 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 (rhesus monkeys). The effects of MOP antagonist (naltrexone), NOP antagonist [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)], and NOP agonists [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one (Ro 64-6198) and 3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (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 to 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 pK(B) values of naltrexone (8.1-8.3) confirmed that MOP receptors mediated mainly 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 the activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, the coactivation 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.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA.
authors: Colette M
authors: CM
authors: Cremeans
authors: Erin
authors: E
authors: Gruley
authors: Donald J
authors: DJ
authors: Kyle
authors: Mei-Chuan
authors: MC
authors: Ko
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002047:Buprenorphine / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D018847:Opioid Peptides / Q000819:agonists / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D053961:Azabicyclo Compounds; D002047:Buprenorphine; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C530605:8-(bis(2-methylphenyl)methyl)-3-phenyl-8-azabicyclo(3.2.1)octan-3-ol