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 mu, kappa, and delta opioid receptor agonist cue.
Male Wistar rats were trained to discriminate either the opioid receptor like (ORL)-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-triazaspiro[4.5]decan-4-one) or morphine from saline using a two-choice, food reinforced, operant procedure. Acquisition of Ro 64-6198 discrimination was relatively slow (mean trials to criterion 113 +/- 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 +/- 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 kappa opioid receptor agonist U50,488 [trans-3,4-dichloro-N-methyl-N(2-[1-pyrrolidinyl]cyclohexyl) benzeneacetamide methanesulfonate] (0.3-6 mg/kg s.c.) and the delta opioid receptor agonist SNC-80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (0.3-6 mg/kg i.p.) failed to evoke significant generalization to either cue. The mu 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.
Recker
Matthew D
MD
K15-2-2600, Schering Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
Higgins
Guy A
GA
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013141:Spiro Compounds / Q000494:pharmacology*; D000094942:Nociceptin Receptor
D001562:Benzimidazoles; D007093:Imidazoles; D009020:Morphine; D010880:Piperidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C402921:J 113397; C408068:Ro 64-6198; C000722285:Oprl1 protein, rat