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.
Tokuyama
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Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216, USA.
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D000818:Animals; D002077:Butorphanol / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control
D002121:Calcium Channel Blockers; D009292:Narcotic Antagonists; D009270:Naloxone; D018698:Glutamic Acid; D009020:Morphine; D004110:Diltiazem; D002077:Butorphanol