Reversal of Morphine Antinociceptive Tolerance and Dependence by the Acute Supraspinal Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II

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Abstract
Previous studies have suggested that Ca2+/calmodulin-dependent protein kinase II (CaMKII) can modulate opioid tolerance and dependence via its action on learning and memory. In this study, we examined whether CaMKII could directly regulate opioid tolerance and dependence. CaMKII activity was increased after the treatment with morphine (100 mg/kg s.c. or 75 mg s.c. of morphine/pellet/mouse); the effect exhibited a temporal correction with the development of opioid tolerance and dependence. In mice treated with morphine (100 mg/kg s.c.), morphine tolerance and dependence developed in 2 to 6 h. An acute supraspinal administration of KN93 [2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)], a CaMKII inhibitor, was able to dose-dependently reverse the already-established antinociceptive tolerance to morphine (p < 0.001 for 15-30 nmol; not significant for 5 nmol). KN92 [2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine] (30 nmol i.c.v.), a kinase-inactive analog of KN93, did not affect opioid tolerance. Neither KN92 nor KN93 affected basal nociception or acute morphine antinociception (1-10 nmol i.c.v.). Likewise, dependence on morphine was abolished by the acute administration of KN93, but not KN92, in a dose-dependent manner. Pretreatment of mice with KN93 also prevented the development of morphine tolerance and dependence. The effect of acute CaMKII inhibition was not limited to the particular experimental model, because KN93 also acutely reversed the established opioid tolerance and dependence in mice treated with morphine (75 mg/pellet/mouse s.c.) for 6 days. Taken together, these data strongly support the hypothesis that CaMKII can act as a key and direct factor in promoting opioid tolerance and dependence. Identifying such a direct mechanism may be useful for designing pharmacological treatments for these conditions.

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