Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys.
Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.
Ko
Mei-Chuan
MC
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-5632, USA. mko@umich.edu
Woods
James H
JH
Fantegrossi
William E
WE
Galuska
Chad M
CM
Wichmann
Jürgen
J
Prinssen
Eric P
EP
D015760:Alfentanil / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D002211:Capsaicin; D002491:Central Nervous System Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D007093:Imidazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology; D011537:Pruritus / Q000188:drug therapy; D011957:Receptors, Opioid / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D012054:Reinforcement, Psychology; D012131:Respiratory Insufficiency / Q000188:drug therapy; D013141:Spiro Compounds / Q000494:pharmacology*; D000094942:Nociceptin Receptor
D000701:Analgesics, Opioid; D001562:Benzimidazoles; D002491:Central Nervous System Agents; D007093:Imidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C408068:Ro 64-6198; D013141:Spiro Compounds; D015760:Alfentanil; D009271:Naltrexone; D002211:Capsaicin; D000094942:Nociceptin Receptor