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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 [ 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 ± 0.10 μM) than in synaptosomes from morphine-naive mice (EC 50 = 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.

The activation of specific subtypes of serine/threonine protein phosphatases (PPs) plays a role in the antinociceptive effect of acute morphine, but it is not known whether these enzymes are involved in morphine-induced antinociception in morphine-tolerant animals. We evaluated the effects of both okadaic acid (a selective inhibitor of some serine/threonine PPs) and its inactive analogue L-norokadaone on the antinociception induced by morphine in morphine-naive and -tolerant female mice in the tail-flick test. Okadaic acid (0.01 and 1 pg/mouse, i.c.v.), but not L-norokadaone (1 pg/mouse, i.c.v.), antagonized in a dose-dependent way the antinociception induced by morphine (1–16 mg/kg, s.c.) in morphine-naive animals. However, both okadaic acid (0.01 and 1 pg/mouse, i.c.v.) and L-norokadaone (1 pg/mouse, i.c.v.) were unable to modify the antinociceptive effect of morphine in morphine-tolerant mice. These results suggest that in morphine-induced thermal analgesia, the role of serine/threonine PPs highly sensitive to okadaic acid is different in morphine-tolerant and morphine-naive female mice.

We showed that glibenclamide, a blocker of ATP-dependent potassium channels in the CNS, antagonizes morphine-induced analgesia in mice