title: Ex vivo determination of opiate antagonist binding at mu-opioid ([3H]-DAGO) receptors in hypothalamic micropunches from maturing female rats: comparison between SDZ 210-096 and nalmefene.
abstract: We have previously shown that the duration of opioid receptor blockade is critical in determining the degree of opioid antagonist effect following peripheral injection of naloxone and naltrexone. In the present work, we have used this ex vivo technique to compare receptor occupancy of a new opiate antagonist, SDZ 210-096 (SDZ), to that of nalmefene (NLM) in maturing female rats. Two doses (SDZ, 5.6 and 50 mg/kg; NLM, 2.5 and 50 mg/kg) were injected subcutaneously into 3 groups of rats (infantile, juvenile and peripubertal). Micropunches from hypothalamic coronal slices (300 microns) were removed at various times post-injection for quantification of mu-opioid receptors with [3H]-DAGO. Acute administration of the lower dose of SDZ inhibited ligand binding almost completely by 3 h but 50% recovery was observed in all age groups by 12 h. In contrast, SDZ 50 mg/kg provided 80-100% antagonism for at least 24 h. Age-related differences in the ability of SDZ to inhibit [3H]-DAGO binding were observed in that hypothalamic mu-opioid receptors were blocked for longer periods in younger rats. Determination of receptor occupation following NLM injection confirmed that it too has prolonged duration of action but a 24 h blockade is not achieved with either dose of this antagonist. Age-related and dose-related changes in receptor occupancy were minimal compared to SDZ. These studies clarify the interaction of these antagonists at hypothalamic mu-opioid receptors and provide information which allows a clearer interpretation of results in experiments involving opioid blockade.
authors.affiliation: Department of Obstetrics, Gynecology, Physiology, Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Landymore
authors.forename: A
authors.initials: A
authors.lastname: Giles
authors.forename: M
authors.initials: M
authors.lastname: Wilkinson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D009019:Morphinans / Q000378:metabolism* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains / Q000254:growth & development; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D012741:Sexual Maturation / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000254:growth & development
chemical_list: D004745:Enkephalins; D009019:Morphinans; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059335:SDZ 210-096; D009271:Naltrexone; C038981:nalmefene