Opioid receptor antagonist nalmefene stereospecifically inhibits glutamate release during global cerebral ischemia.
The opioid receptor antagonist nalmefene improves cellular bioenergetics and attenuates the reduction in tissue glutamate levels after global cerebral ischemia/reperfusion. The latter finding suggests that nalmefene might inhibit glutamate release during ischemia. To test this hypothesis, we used microdialysis techniques to examine the effect of nalmefene pretreatment on extracellular excitatory amino acid levels during global cerebral ischemia in rats. Saline, (-)-nalmefene (20, 100 or 500 micrograms/kg) or the inactive nalmefene enantiomer (+)-nalmefene (100 micrograms/kg) were given 15 min prior to induction of ischemia using a multi-vessel occlusion model. Pretreatment with (-)-nalmefene decreased peak dialysate glutamate in a dose-dependent fashion as compared to saline-treated controls, whereas (+)-nalmefene had no effect. These results suggest that opioid receptors may modulate glutamate release during ischemia and that inhibition of excitatory amino acid release may contribute to the protective actions of opioid receptor antagonists in cerebral ischemia.
Graham
S H
SH
Department of Neurology, University of California at San Francisco 94121.
Shimizu
H
H
Newman
A
A
Weinstein
P
P
Faden
A I
AI
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D005998:Glycine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013237:Stereoisomerism; D013654:Taurine / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D009292:Narcotic Antagonists; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D009271:Naltrexone; D005998:Glycine; C038981:nalmefene