Morphine inhibits glutamate exocytosis from rat cerebral cortex nerve terminals (synaptosomes) by reducing Ca2+ influx.
Morphine, a mu-opioid agonist, suppressed the Ca(2+)-dependent release of glutamate that was evoked by exposing cerebrocortical synaptosomes to the potassium channel blocker 4-aminopyridine. The presynaptic inhibition produced by morphine was concentration-dependent and blocked by the nonselective opioid receptor antagonist naloxone. As determined by examining the mechanism of mu-opioid receptor-mediated inhibition of glutamate release, morphine caused a significant reduction in 4-aminopyridine-evoked increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](c)), but failed to alter both 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential and Ca(2+) ionophore (ionomycin)-induced glutamate release. In addition, morphine was not capable of producing further inhibition on 4AP-evoked glutamate release in synaptosomes pretreated with the cannabinoid CB(1) receptor agonist WIN 55212-2, which has been shown to depress glutamate release through a suppression of presynaptic voltage-dependent Ca(2+) channel activity. These data suggest that morphine exerts its inhibitory effect presynaptically, likely through the reduction of Ca(2+) influx into nerve terminals, and thereby inhibits the release of glutamate in the cerebral cortex. This may therefore indicate that mu-opioid receptor agonists have neuroprotective properties, especially in the excessive glutamate release that occurs under certain pathological conditions.
Yang
Tsung-Tsair
TT
Department of Mental Health, Cardinal Tien Hospital, Taipei, Taiwan 231.
Hung
Chi-Feng
CF
Lee
Yih-Jing
YJ
Su
Ming-Jai
MJ
Wang
Su-Jane
SJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002232:Carbocyanines / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects*; D005470:Fluorometry / Q000379:methods; D016257:Fura-2 / Q000031:analogs & derivatives* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D052160:Benzothiazoles; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002232:Carbocyanines; D007476:Ionophores; D009025:Morpholines; D009281:Naphthalenes; D009292:Narcotic Antagonists; D026902:Potassium Channel Blockers; C049925:fura-2-am; D009270:Naloxone; D018698:Glutamic Acid; C012944:3,3'-dipropyl-2,2'-thiadicarbocyanine; D015759:Ionomycin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009020:Morphine; D015761:4-Aminopyridine; D002118:Calcium; D016257:Fura-2