RT Journal Article
SR Electronic
T1 The Opioid Receptor Like-1 Receptor Agonist Ro 64-6198 (1<em>S</em>,3<em>aS</em>-8-2,3,3<em>a</em>,4,5,6-Hexahydro-1<em>H</em>-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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 652
OP 658
DO 10.1124/jpet.104.071423
VO 311
IS 2
A1 Recker, Matthew D.
A1 Higgins, Guy A.
YR 2004
UL http://jpet.aspetjournals.org/content/311/2/652.abstract
AB 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 (ED50 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 (ED50 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 κ 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 δ opioid receptor agonist SNC-80 [(+)-4-[(αR)-α-((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 μ 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 (ED50 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. The American Society for Pharmacology and Experimental Therapeutics