The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys.
BACKGROUND
The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward.


OBJECTIVE
The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys.


RESULTS
Ro 64-6198 (0.001-0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50°C water) in the absence of sedation, whereas diazepam (0.32-3.2 mg/kg, i.v.) did not have analgesic effects without sedation. Diazepam (1.0-5.6 mg/kg, i.v.) and the largest dose of Ro 64-6198 (0.32 mg/kg, i.v.) decreased lever pressing maintained by intravenous self-administration of the mu-opioid agonist, remifentanil, but neither effect could be distinguished from sedative effects. Although neither drug consistently increased responding during nonreinforcement, such effects were observed more frequently following diazepam administration. The effects of Ro 64-6198 on lever pressing were blocked by the NOP-receptor antagonist, J-113397, but not by the benzodiazepine antagonist, flumazenil.


CONCLUSIONS
These findings suggest that the effects of Ro 64-6198 on operant lever pressing are mediated by NOP receptors and that larger doses are required to impact operant behavior when compared directly with those that produce antinociception. Therefore, the present findings support previous literature suggesting NOP receptors are a viable target for pain management.
Podlesnik
Christopher A
CA
Department of Pharmacology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109-5632, USA. cpod@umich.edu
Ko
Mei-Chuan
MC
Winger
Gail
G
Wichmann
Jürgen
J
Prinssen
Eric P
EP
Woods
James H
JH
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009292:Narcotic Antagonists; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000819:agonists*; D000077208:Remifentanil; D012646:Self Administration / Q000379:methods; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000094942:Nociceptin Receptor
D001562:Benzimidazoles; D007093:Imidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; D000077208:Remifentanil; D003975:Diazepam; D000094942:Nociceptin Receptor