Inhibition of Calcium/Calmodulin-Dependent Protein Kinase II in Rat Hippocampus Attenuates Morphine Tolerance and Dependence
- 1Shanghai Institute of Cell Biology, Chinese Academy of Sciences (G.H.F, G.P.); 2National 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
Abstract
Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findings that calcium/calmodulin-dependent protein kinase II (CaMKII) is essential in learning and memory processes, and morphine treatment increases CaMKII activity in hippocampus, the present study was undertaken to examine whether inhibition of hippocampal CaMKII prevents morphine tolerance and dependence. Here, we report that inhibition of CaMKII by intrahippocampal dentate gyrus administration of the specific inhibitors KN-62 and KN-93 to rats significantly attenuated the tolerance to the analgesic effect of morphine and the abstinence syndrome precipitated by opiate antagonist naloxone. In contrast, both KN-04 and KN-92, the inactive structural analogs of KN-62 and KN-93, failed to attenuate morphine tolerance and dependence, indicating that the observed effects of KN-62 and KN-93 are mediated through inhibition of CaMKII. Furthermore, administration of CaMKII antisense oligonucleotide into rat hippocampal dentate gyrus, which decreased the expression of CaMKII specifically, also attenuated morphine tolerance and dependence, while the corresponding sense oligonucleotide of CaMKII did not exhibit such inhibitory effect. Moreover, the KN-62 treatment abolished the rewarding properties of morphine as measured by the conditioned place preference. These results suggest that hippocampal CaMKII is critically involved in the development of morphine tolerance and dependence, and inhibition of this kinase may have some therapeutic benefit in the treatment of opiate tolerance and dependence.
Footnotes
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Send reprint requests to: Dr. Gang Pei, Shanghai Institute of Cell Biology, Chinese Academy of Sciences, 320 Yue Yang Rd., Shanghai 200031, P.R. China. E-mail: gangpei{at}sunm.shcnc.ac.cn
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This work was supported by research grants from National Natural Science Foundation of China (39630130, 39825110, and 39625015), Chinese Academy of Sciences, Shanghai Research Center of Life Sciences, Shanghai Educational Development Foundation and German Max-Planck Society.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- NOS
- nitric oxide synthase
- CaMKII
- calcium/calmodulin-dependent protein kinase II
- KN-62
- 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-trosyl]-4-phenylpiperazine
- KN-04
- [N-(1–1[P-(5-isoquinolinsulfonyl)benzyl]-2-(4-phenylpiperazinyl) ethyl)-5-isoquinolinsulfonamide
- KN-93
- N-[2-(N-(4-chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-methoxybenzenesulfnamide
- KN-92
- 2-[N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, phosphate
- MAPK, mitogen-activated protein kinase.
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- Received January 27, 1999.
- Accepted April 20, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
