The Opioid Receptor Like-1 Receptor Agonist Ro 64-6198 (1S,3aS-8-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one) Produces a Discriminative Stimulus in Rats Distinct from That of a μ, κ, and δ Opioid Receptor Agonist Cue

Abstract

Male Wistar rats were trained to discriminate either the opioid receptor like (ORL)-1 receptor agonist 3,3a,4,5,3,decan-4-one) or morphine from saline using a twochoice, food reinforced, operant procedure. Acquisition of Ro 64-6198 discrimination was relatively slow (mean trials to criterion 113 Ϯ 6), and a final 4 mg/kg dose (initial training dose 2 mg/kg) was required to establish appropriate stimulus control. In comparison, a separate group of rats attained a morphine (2 mg/kg) discrimination in 44 Ϯ 4 trials. In tests of substitution, Ro 64-6198 produced a dose-related generalization to its own cue (ED 50 of 1.1 mg/kg i.p.), yet only weakly generalized to the morphine cue (19% at 10 mg/kg i.p.). In contrast, morphine generalized completely to the morphine cue (ED 50 of 0.7 mg/kg s.c.), yet only partially generalized to the Ro 64-6198 cue (40% at 6 mg/kg s.c.). The opioid receptor agonist U50,488 [trans-3,4-(0.3-6 mg/kg s.c.) and the ␦ opioid receptor agonist SNC-803-6 mg/kg i.p.) failed to evoke significant generalization to either cue. The opioid receptor agonists codeine (0.3-20 mg/kg) and buprenorphine (0.01-1 mg/kg) completely generalized to the morphine cue, but only buprenorphine partially generalized to the Ro 64-6198 cue. Naloxone pretreatment completely blocked the morphine cue (ED 50 of 0.005 mg/kg s.c.), yet only weakly attenuated the Ro 64-6198 cue at 0.3 mg/kg. Finally, the selective ORL-1 antagonist J-113397 [1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one] completely blocked the Ro 64-6198 cue at a dose (30 mg/kg i.p.) that had no effect against the morphine cue. The present studies demonstrate that rats may be trained to discriminate Ro 64-6198 from saline, and the pharmacological characteristics of this cue are most consistent with ORL-1 receptor activation.Opioid receptors are currently classified into four subclasses, the ␦ opioid peptide receptor, opioid peptide receptor, opioid peptide receptor, and the nociceptin/orphaninFQ peptide receptor (also termed ORL-1) subclass (Calo et al., 2000;Snyder and Pasternak, 2003). The ORL-1 receptor represents the most recent addition to this family, identified by various laboratories during efforts to clone subtypes to the , , or ␦ receptor subclasses (for recent reviews, see Calo et al., 2000;Mogil and Pasternak, 2001).The ORL-1 receptor has a pharmacology that is clearly distinct from the other opioid subclasses. For example, naloxone, a relatively nonselective antagonist at , , and ␦ receptors, has low affinity for the ORL-1 subtype (Calo et al., 2000;Mogil and Pasternak, 2001). Furthermore, nonpeptide ligands apparently selective for the ORL-1 receptor have been identified, notably the agonist Ro 64-6198 (Jenck et al., 2000), and the antagonist J-113397 (Ozaki et al., 2000). Ro 64-6198 seems to function as a full agonist, equivalent to the likely endogenous agonist orphaninFQ/nociceptin (OFQ/N; Calo et al., 2000) in cell-based systems expressing the human ORL-1 receptor, and with at le...

Further characterization of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198 in rodent models of conflict anxiety and despair

“…The anxiolytic effect was attenuated by the NOP receptor antagonist J-113397, which had no effects on punished drinking per se. Although in our hands, the anxiolytic effects of Ro 64-6198 were only partially blocked by J-113397, this data confirm previous pharmacological evidence, with J-113397 (Ko et al 2009;Recker and Higgins 2004;Varty et al 2005) as well as genetic evidence in NOP receptor knockout animals (Higgins et al 2001;Reiss et al 2008;Varty et al 2005), indicating that the behavioral effects of the currently used doses of Ro 64-6198 are exclusively mediated by the NOP receptor. Moreover, it is unlikely that the anxiolytic properties of Ro 64-6198 in the VCT are related to other NOP receptor-mediated functions such as pain control or diuresis (for review see Chiou et al 2007, Shoblock 2007.…”

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…94 This discriminative stimulus was not as strong as that produced by mu opioid agonists, suggesting that NOP agonists are likely to be devoid of reinforcing or euphorigenic effects. In nonhuman primates, 8 did not produce reinforcing effects at doses at which it showed significant antinociceptive effects.…”

Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

“…Rats trained to discriminate Ro 64-6198 from saline, morphine 6 mg/kg, and buprenorphine 0.1 mg/kg, produced 40%-50% responding on the drug-appropriate lever, but these doses significantly suppressed rates of responding, and there was considerable variability among subjects (Recker and Higgins, 2004). This is consistent with the present study in that Ro 64-6198-trained monkeys responded on the drug-appropriate lever when tested with doses of fentanyl and buprenorphine that also suppressed rates of responding, except that neither drug met criteria for generalization.…”

“…Previous research has established that agonist stimulation of MOP, DOP, and KOP produced discriminative stimulus effects that are pharmacologically selective Colpaert, 1999). Previous drug discrimination studies with Ro 64-6198 in rats showed that it possessed stimulus properties that were unlike opioid agonists at MOP, DOP, and KOP (Recker and Higgins, 2004). These effects were selectively blocked with the NOP antagonist, J-113397, but not with the opioid antagonist naltrexone.…”