Effects of diltiazem,a Ca2+ channel blocker,on naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats

The effects of diltiazem, an L-type Ca²⁺ channel blocker, on naloxone (an opioid receptor antagonist)-precipitated withdrawal signs and changes in extracellular levels of dopamine (DA) and its metabolites in various brain regions of morphine (a -opioid receptor agonist) or butorphanol (a// mixed opioid receptor agonist) dependent rats were investigated using high performance liquid chromatography fitted with an electrochemical detector (HPLC-ED). Rats were rendered opioid-dependent by continuous intracerebroventricular (ICV) infusion with morphine (26 nmol/µl per h) or butorphanol (26 nmol/µ1 per h) for 3 days. The expression of physical dependence produced by these opioids, as evaluated by naloxone (5 mg/kg, IP)-precipitated withdrawal signs, was reduced by concomitant infusion of diltiazem (10 and 100 nmol/µl per h). Under the same condition, naloxone 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, and midbrain regions. In animals rendered dependent on butorphanol, the results obtained were similar to those of morphine-dependent rats except for the changes in DOPAC levels. Furthermore, concomitant infusion of diltiazem and opioids blocked the decreases in levels of DA, DOPAC, and HVA in a dosedependent manner. These results suggest that the augmentation of intracellular Ca²⁺ mediated through L-type Ca²⁺ channels during continuous opioid infusion results in a decrease in extracellular levels of DA and its metabolites in some specific regions, which are intimately involved in the expression of withdrawal syndrome precipitated by naloxone.