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

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.

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

“…This possibility is supported by our observations that these receptors are co-expressed in CeA neurons, and other reports that μOR activation has direct inhibitory actions on excitatory postsynaptic signaling in CeA neurons (Zhu and Pan, 2004). Morphine initiates an array of intracellular transduction pathways involving intracellular calcium, cAMP, protein kinases (Bernstein and Welch, 1998;Fan et al, 1999;Lim et al, 2005) and transcription factors (Rasmussen et al, 1995;Shaw-Lutchman et al, 2002). These pathways may impact intermediate-and longterm cellular processes including gene expression (Ammon-Treiber and Hollt, 2005), glutamate receptor trafficking (Glass et al, 2003;Glass et al, 2005), or neuronal morphology (Robinson and Kolb, 2004).…”

Ohmefentanyl stereoisomers induce changes of CREB phosphorylation in hippocampus of mice in conditioned place preference paradigm

“…withdrawal [24][25][26]. The present study demonstrates that morphine, F9202 and F9204 significantly stimulate CREB phosphorylation and maintain for a long time in hippocampus of CPP mice.…”

Involvement of pCREB Expression in Inhibitory Effects of Coptis japonica on Morphine-induced Psychological Dependence

“…CERB has been implicated in the formation of long-term memory and CREB-mediated transcription in the hippocampus is related to learning and memory (Deisseroth et al, 1996). Also it is well known that hippocampus play a key role in tolerance, dependence, and withdrawal (Fan et al, 1999;Lou et al, 1999). The development of CPP is deeply related to a kind of the memory process combined with environmental cue and drug.…”