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

Neuropsychopharmacology. 2009 Aug;34(9):2088-96. doi: 10.1038/npp.2009.33. Epub 2009 Mar 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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
  • Pain / drug therapy
  • Piperidines / pharmacology
  • Pruritus / drug therapy
  • Receptors, Opioid / agonists*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism
  • Reinforcement, Psychology
  • Respiratory Insufficiency / drug therapy
  • Spiro Compounds / pharmacology*

Substances

  • 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
  • nociceptin receptor
  • Capsaicin