title: Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys.
abstract: Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.) sacconep@umich.edu.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Saccone
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Zelenock
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lindsey
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sulima
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Eric P
authors.initials: EP
authors.lastname: Prinssen
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wichmann
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (P.A.S., K.A.Z., A.M.L., J.H.W.); National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (A.S., K.C.R.); and Hoffman- La Roche Ltd., Basel, Switzerland (E.P.P., J.W.).
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; D001562:Benzimidazoles; D018757:GABA Modulators; D007093:Imidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; D009271:Naltrexone; D003975:Diazepam; D005283:Fentanyl; D000094942:Nociceptin Receptor