|| Checking for direct PDF access through Ovid
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, 45 mg/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 [3H]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 α1 and α3 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 (EC50 = 1.79 ± 0.10 μM) than in synaptosomes from morphine-naive mice (EC50 = 0.69 ± 0.12 μM). 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 10 ng/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.