Central discriminative effects of morphine in rats: training via intracerebroventricular administration

Abstract

There have been studies of the discriminative effects of intracerebroventricularly (ICV)-administered morphine (MOR) in rats trained to discriminate MOR systemically, but the converse has not been done. In this study, rats were trained to discriminate between ICV (1–10 μg/3 μl, 1 h) or subcutaneous (SC) (3.0 mg/kg, 30 min) injections of MOR vs. saline/vehicle in a discrete-trial avoidance/escape procedure. On generalization testing, subjects in both the ICV- and SC-trained groups responded on the MOR-appropriate lever at ICV MOR doses ≤1–3 μg, and at SC MOR doses 2 to 3 orders of magnitude higher (vs. ICV). Naltrexone (SC) blocked the stimulus effects of MOR (ICV) equipotently in both training groups. In ICV-trained subjects, levorphanol (SC), the μ-opioid selective peptide [D-Ala 2, NMePhe 4, Gly-ol]-enkephalin (DAMGO) (ICV), and the enkephalinase inhibitor N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-β-alanine (SCH 32615) (ICV) produced complete MOR-appropriate responding, whereas the dextrorotary enantiomer of levorphanol dextrorphan (SC; ≤ 3.0 mg/kg) and the δ-opioid selective peptide [D-Pen 2, D-Pen 5]-enkephalin (DPDPE) (ICV, ≤ 0.03 mg) did not. SC-trained subjects did not generalize to SCH 32615, which suggests qualitative differences in the discriminative stimulus effects of novel drugs as a function of the route of administration of the training drug. These data demonstrate that it is feasible to train rats to discriminate an opioid administered by the ICV route, and to perform extended tests of generalization to novel drugs (SC or ICV) in rats so trained.