The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex.
Administration of morphine-3-glucuronide (M3G) by the intracerebroventricular (i.c.v.) route in doses of 2-8 micrograms produced a marked dose-dependent behavioural excitation in adult Sprague-Dawley rats. When LY274614 (1-50 ng i.c.v.) or midazolam maleate (25-50 micrograms i.c.v.) was administered 20 min prior to a maximal excitatory dose of M3G (7 micrograms), all excitatory behaviours were reduced. In contrast, when LY274614 (200 ng i.c.v.) was given after M3G (7 micrograms), it did not reduce all of the excitatory behaviours. Since we have also shown in in vitro binding studies that M3G has very low affinity for the known binding sites on the N-methyl-D-aspartate (NMDA) and the gamma-amino-butyric acid (GABAA) receptor complexes (1), the results of this study suggest that the anti-convulsant compounds, LY274614 and midazolam, are functional antagonists of the excitatory effects of M3G. LY274614 (1-50 ng i.c.v.) and midazolam (25-50 micrograms i.c.v.) did not produce significant behavioural excitation and phenyclidine (PCP)-type effects were not observed. This contrasts with the NMDA receptor antagonists CGS19755 and MK801, where PCP-type effects have been reported to interfere with behavioural assessment. Morphine hydrochloride in a maximal analgesic dose (50 micrograms i.c.v.), did not reduce the excitation score of a maximal excitatory dose of M3G (7 micrograms), lending support to the view that M3G's excitatory effects are elicited through a non-opioid mechanism.
Bartlett
S E
SE
Department of Pharmacy, University of Queensland, Brisbane, Australia.
Cramond
T
T
Smith
M T
MT
D017109:Akathisia, Drug-Induced / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013047:Specific Pathogen-Free Organisms
D007546:Isoquinolines; D009022:Morphine Derivatives; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; C070935:LY 274614; C018108:morphine-3-glucuronide; D008874:Midazolam