title: Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide.
abstract: Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were given intracerebroventricularly (i.c.v.) to rats. The antinociceptive effects were assessed in the tail-flick and hot-plate tests as well as the writhing test. Ventilatory effects were studied in halothane-anaesthetized rats. Based on calculated ED50 values, morphine-6-glucuronide was approximately 200 times more potent that morphine itself in the tail-flick and hot-plate tests. In the writhing test the difference in ED50 was approximately 9-fold. Morphine and morphine-6-glucuronide administered i.c.v. induced dose-related decreases in minute ventilation in the dose range 2.7 x 10(-9)-1.3 x 10(-7) mol. The dose-response curve for minute ventilation was steeper for morphine-6-glucuronide than for morphine. Morphine-6-glucuronide was approximately 10 times more potent than morphine in depressing minute ventilation. Morphine-6-glucuronide reduced both tidal volume and respiratory frequency, while morphine reduced only the tidal volume. Morphine-3-glucuronide, in contrast, increased both tidal volume and respiratory frequency, causing an increase in minute ventilation. Apnoea was elicited after the highest doses of morphine-6-glucuronide but not of morphine. The potency difference for depression of minute ventilation between morphine-6-glucuronide and morphine corresponded well to the difference in the writhing test but not to the potency difference in the tail-flick or hot-plate tests. The ventilatory depression induced by morphine and morphine-6-glucuronide was readily reversed by naloxone, while the hyperventilation caused by morphine-3-glucuronide was slightly potentiated by the opioid antagonist. Naloxone pretreatment completely blocked the ventilatory depression induced by morphine-6-glucuronide. These results show that the potent ventilatory depression induced by morphine-6-glucuronide is related to its antinociceptive effects in rats. Furthermore, the fact that morphine-3-glucuronide stimulated ventilation and that morphine had a more shallow ventilatory dose-response curve compared to morphine-6-glucuronide may indicate that morphine-3-glucuronide is a functional antagonist of the depressive effects of morphine and morphine-6-glucuronide on ventilation.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology and Anesthesiology, University of Gothenburg, Sweden.
authors.forename: Q L
authors.initials: QL
authors.lastname: Gong
authors.forename: T
authors.initials: T
authors.lastname: Hedner
authors.forename: J
authors.initials: J
authors.lastname: Hedner
authors.forename: R
authors.initials: R
authors.lastname: Björkman
authors.forename: G
authors.initials: G
authors.lastname: Nordberg
mesh_terms: D000700:Analgesics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D009022:Morphine Derivatives / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D012119:Respiration / Q000187:drug effects*
chemical_list: D000700:Analgesics; D009022:Morphine Derivatives; D009270:Naloxone; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide