A protein kinase inhibitor, H-7, blocks naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats

The influence of an inhibitor of cAMP-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine], on naloxone tan opioid receptor antagonist)-precipitated withdrawal signs and changes i n levels of dopamine IDA) and its metabolites in morphine- or butorphanol-d ependent rats was investigated. Animals were infused continuously with morp hine (a mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa mixed opioid receptor agonist) for 3 days, Naloxone precipitated withdrawal syndr ome and decreased the levels of DA in the cortex, striatum, and midbrain; 3 ,4-dihydroxyphenylacetic acid (DOPAC) in the cortex, striatum, limbic areas , and midbrain; and homovanilic acid (HVA) in the striatum, limbic areas, a nd midbrain regions, In animals rendered dependent on butorphanol, the resu lts obtained were similar to those of morphine-dependent rats except for th e changes in DOPAC levels, Concomitant infusion of H-7 and opioid blocked b oth the expression of withdrawal signs and the decreases in DA, DOPAC, and HVA levels in a dose-dependent manner, These results suggest that the enhan cement of cAMP-dependent protein kinase and/or protein kinase C activity ac companying the increase of DA neuron activity during continuous infusion of opioids leads to an abrupt reduction in levels of DA and its metabolites p recipitated by naloxone, which is intimately involved in the expression of physical dependence on opioids, (C) 2000 Elsevier Science Inc.