Inhibition of Calcium/Calmodulin-Dependent Protein Kinase II in Rat Hippocampus Attenuates Morphine Tolerance and Dependence

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Vol. 56, Issue 1, 39-45, July 1999

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase II in Rat Hippocampus Attenuates Morphine Tolerance and Dependence

Guo-Huang Fan, Ling-Zhi Wang, Hao-Chun Qiu, Lan Ma, and Gang Pei

Shanghai Institute of Cell Biology, Chinese Academy of Sciences (G.H.F, G.P.); National Laboratory of Medical Neurobiology and Department of Neurobiology, Shanghai Medical University (L.Z.W., H.C.Q., L.M.), Shanghai, People's Republic of China

Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findingsthat calcium/calmodulin-dependent protein kinase II (CaMKII) isessential in learning and memory processes, and morphine treatmentincreases CaMKII activity in hippocampus, the present study wasundertaken to examine whether inhibition of hippocampal CaMKIIprevents morphine tolerance and dependence. Here, we report thatinhibition of CaMKII by intrahippocampal dentate gyrus administrationof the specific inhibitors KN-62 and KN-93 to rats significantlyattenuated the tolerance to the analgesic effect of morphine andthe abstinence syndrome precipitated by opiate antagonist naloxone.In contrast, both KN-04 and KN-92, the inactive structural analogsof KN-62 and KN-93, failed to attenuate morphine tolerance anddependence, indicating that the observed effects of KN-62 andKN-93 are mediated through inhibition of CaMKII. Furthermore,administration of CaMKII antisense oligonucleotide into rat hippocampaldentate gyrus, which decreased the expression of CaMKII specifically,also attenuated morphine tolerance and dependence, while the correspondingsense oligonucleotide of CaMKII did not exhibit such inhibitoryeffect. Moreover, the KN-62 treatment abolished the rewardingproperties of morphine as measured by the conditioned place preference.These results suggest that hippocampal CaMKII is critically involvedin the development of morphine tolerance and dependence, and inhibitionof this kinase may have some therapeutic benefit in the treatmentof opiate tolerance anddependence.

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