Central discriminative effects of morphine in rats: training via intracerebroventricular administration.
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 microg/3 microl, 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 < or =1-3 microg, 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 mu-opioid selective peptide [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAMGO) (ICV), and the enkephalinase inhibitor N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (SCH 32615) (ICV) produced complete MOR-appropriate responding, whereas the dextrorotary enantiomer of levorphanol dextrorphan (SC; < or = 3.0 mg/kg) and the delta-opioid selective peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE) (ICV, < or = 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.
Easterling
K W
KW
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA. keaster@emory.edu
Holtzman
S G
SG
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism
D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D018847:Opioid Peptides; D011957:Receptors, Opioid; D009271:Naltrexone; D009020:Morphine