Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys.

Abstract

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.

• Authors: Mei-Chuan Ko, James H Woods, William E Fantegrossi, Chad M Galuska, Jürgen Wichmann, Eric P Prinssen
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 34 Issue 9 Pg. 2088-96 (Aug 2009) ISSN: 1740-634X [Electronic] England
• PMID: 19279568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Analgesics, Opioid
• Benzimidazoles
• Central Nervous System Agents
• Imidazoles
• J 113397
• Narcotic Antagonists
• Piperidines
• Receptors, Opioid
• Receptors, Opioid, mu
• Ro 64-6198
• Spiro Compounds
• Alfentanil
• Naltrexone
• Capsaicin
• Nociceptin Receptor

Topics

• Alfentanil (pharmacology)
• Analgesics, Opioid (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Benzimidazoles (pharmacology)
• Capsaicin
• Central Nervous System Agents (pharmacology)
• Dose-Response Relationship, Drug
• Female
• Hot Temperature
• Imidazoles (pharmacology)
• Macaca mulatta
• Male
• Naltrexone (pharmacology)
• Narcotic Antagonists (pharmacology)
• Pain (chemically induced, drug therapy)
• Piperidines (pharmacology)
• Pruritus (drug therapy)
• Receptors, Opioid (agonists)
• Receptors, Opioid, mu (agonists, metabolism)
• Reinforcement, Psychology
• Respiratory Insufficiency (drug therapy)
• Spiro Compounds (pharmacology)
• Nociceptin Receptor