Effects of opioid antagonists and morphine in a hippocampal hypoxia/hypoglycemia model.
The influence of opioid antagonists and of morphine on rat hippocampal slices in a model of reversible hypoxia/hypoglycemia was investigated by assessment of evoked field potentials (population spike amplitude). In control slices, a brief hypoxia/hypoglycemia led to a loss of field potentials followed by an impaired recovery (40-50% of baseline) during reperfusion. In contrast, restoration was significantly improved when the opioid receptor antagonists funaltrexamine (mu) or naltrindole (delta) were administered prior to and during hypoxia/hypoglycemia. In addition, recovery was improved in brain slices derived from mu-opioid receptor-deficient mice as compared to wild-type mice, indicating a deleterious role of endogenous opioids in hypoxia/hypoglycemia. Exogenous opiate exposure with morphine (0.1, 1.0, 10 microM) prior to hypoxia/hypoglycemia caused a slight concentration dependent increase of evoked field potentials. When morphine exposure was terminated after 1h and immediately followed by hypoxia/hypoglycemia, an impaired recovery of population spike amplitude was obtained, dependent on morphine concentration during preincubation. These results demonstrate that morphine aggravates neurotoxic effects of hypoxia/hypoglycemia. Conversely, when onset of hypoxia/hypoglycemia was delayed for 3h after morphine termination, a significantly improved recovery was observed. Similarly, in vivo administration of morphine 12h prior to slice preparation resulted in a dose dependent improved recovery of field potentials after hypoxia/hypoglycemia. These results provide evidence that preconditioning with morphine is able to induce neuroprotective effects.
Ammon-Treiber
S
S
Institute of Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany.
Stolze
D
D
Schröder
H
H
Loh
H
H
Höllt
V
V
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D006624:Hippocampus / Q000502:physiology*; D007003:Hypoglycemia / Q000503:physiopathology*; D002534:Hypoxia, Brain / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000523:psychology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; C055382:naltrindole