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

Abstract

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 mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa 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 (i.c.v.) infusion with morphine (26 nmol/microliters per h) or butorphanol (26 nmol/microliters per h) for 3 days. The expression of physical dependence produced by these opioids, as evaluated by naloxone (5 mg/kg. i.p.)-precipitated withdrawal signs, was reduced by concomitant infusion of diltiazem (10 and 100 nmol/microliters 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 dose-dependent 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.

Potentiation by nitric oxide synthase inhibitor and calcium channel blocker of aspartame‐induced antinociception in the mouse formalin test

“…Among them, calcium ions play an important role in neurotransmission and calcium channels are targets for a variety of neurotransmitters, neuromodulators and drugs [34]. Calcium channels are classified into six electrophysiologically and pharmacologically different types of T, L, P, Q, N and R types [35]. It has been noted that L‐type calcium channels play a role in nociceptive activity [1,34].…”

Voltage‐Gated Ion Channels: 6.3 Calcium Channels

“…This crosstalk has also been documented with respect to opioid receptors and Ca 2+ channels (Moises et al, 1994;Bourinet et al, 1996). There are several publications claiming that co-administration of L-type Ca 2+ channel blockers has a positive result with respect to opioidinduced tolerance and/or withdrawal symptoms (Bongianni et al, 1985;Baeyens et al, 1987;Barrios and Baeyens, 1988;Contreras et al, 1988;Alfaro et al, 1990;Antkiewicz-Michaluk et al, 1990;Welch and Olson, 1991;Ruiz et al, 1993;Diaz et al, 1995;Garaulet et al, 1996;Tokuyama and Ho, 1996;Michaluk et al, 1998).…”