Inhibitory effects of diltiazem, an L-type Ca2+ channel blocker, on naloxone-increased glutamate levels in the locus coeruleus of opioid-dependent rats.

To investigate the effects of diltiazem, an L-type Ca2+ channel blocker, on naloxone-precipitated withdrawal and elevations of glutamate levels in the locus coeruleus (LC) of opioid-dependent rats, animals were continuously infused with 26 nmol/microliter/h of morphine or butorphanol intracerebroventricularly (i.c.v.) via osmotic minipumps for 3 days. I.c.v. injection of naloxone (an opioid-receptor antagonist, 48 nmol/5 microliters) precipitated withdrawal signs and increased extracellular fluid levels of glutamate in the LC of morphine- or butorphanol-dependent rats measured by in vivo microdialysis. Meanwhile, concomitant infusion of opioids with diltiazem (10 or 100 nmol/microliter/h) inhibited the withdrawal signs and prevented the elevations of glutamate levels in the LC. These results suggest that an expeditious release of glutamate in the LC region regulated by L-type Ca2+ channels mediated system plays a role in the expression of withdrawal signs from opioids.