Changes in morphine-induced activation of cerebral Na(+),K(+)-ATPase during morphine tolerance: biochemical and behavioral consequences

Biochem Pharmacol. 2012 Jun 1;83(11):1572-81. doi: 10.1016/j.bcp.2012.02.023. Epub 2012 Mar 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / antagonists & inhibitors
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cerebrum / enzymology*
  • Drug Tolerance / physiology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Mice
  • Morphine / antagonists & inhibitors
  • Morphine / pharmacology*
  • Ouabain / pharmacology
  • Pain / drug therapy
  • Protein Subunits
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / enzymology

Substances

  • Analgesics, Opioid
  • Enzyme Inhibitors
  • Protein Subunits
  • Ouabain
  • Morphine
  • Sodium-Potassium-Exchanging ATPase