title: Changes in morphine-induced activation of cerebral Na(+),K(+)-ATPase during morphine tolerance: biochemical and behavioral consequences.
abstract: There is ample evidence of the biological changes produced by the sustained activation of opioid receptors. We evaluated the adaptive changes of cerebral Na(+),K(+)-ATPase in response to the sustained administration of morphine (minipumps, 45mg/kg/day, 6 days) in CD-1 mice and the functional role of these changes in opioid antinociception. The antinociceptive effect of morphine as determined with tail-flick tests was reduced in morphine-tolerant mice. There were no significant changes in the density of high-affinity Na(+),K(+)-ATPase α subunits labeled with [(3)H]ouabain in forebrain membranes from morphine-tolerant compared to those of morphine-naive animals. Western blot analysis showed that there were no significant differences between groups in the changes in relative abundance of α(1) and α(3) subunits of Na(+),K(+)-ATPase in the spinal cord or forebrain. However, the morphine-induced stimulation of Na(+),K(+)-ATPase activity was significantly lower in brain synaptosomes from morphine-tolerant mice (EC(50)=1.79±0.10μM) than in synaptosomes from morphine-naive mice (EC(50)=0.69±0.12μM). Furthermore, adaptive alterations in the time-course of basal Na(+),K(+)-ATPase activity were observed after sustained morphine treatment, with a change from a bi-exponential decay model (morphine-naive mice) to a mono-exponential model (morphine-tolerant mice). In behavioral studies the antinociceptive effects of morphine (s.c.) in the tail-flick test were dose-dependently antagonized by ouabain (1 and 10ng/mouse, i.c.v.) in morphine-naive mice, but not in morphine-tolerant mice. These findings suggest that during morphine tolerance, adaptive cellular changes take place in cerebral Na(+),K(+)-ATPase activity which are of functional relevance for morphine-induced antinociception.
authors.affiliation: Department of Pharmacology and Neurosciences Institute, University of Granada, Granada, Spain.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Gonzalez
authors.forename: Willias
authors.initials: W
authors.lastname: Masocha
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Fernández
authors.forename: Ahmad
authors.initials: A
authors.lastname: Agil
authors.forename: Maria
authors.initials: M
authors.lastname: Ocaña
authors.forename: Esperanza
authors.initials: E
authors.lastname: Del Pozo
authors.forename: José M
authors.initials: JM
authors.lastname: Baeyens
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D054022:Cerebrum / Q000201:enzymology*; D004361:Drug Tolerance / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D010042:Ouabain; D009020:Morphine; D000254:Sodium-Potassium-Exchanging ATPase