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delta-Opioid receptor antagonism induces NMDA receptor-dependent excitotoxicity in anoxic turtle cortex.

Abstract
delta-Opioid receptor (DOR) activation is neuroprotective against short-term anoxic insults in the mammalian brain. This protection may be conferred by inhibition of N-methyl-d-aspartate receptors (NMDARs), whose over-activation during anoxia otherwise leads to a deleterious accumulation of cytosolic calcium ([Ca(2+)](c)), severe membrane potential (E(m)) depolarization and excitotoxic cell death (ECD). Conversely, NMDAR activity is decreased by approximately 50% with anoxia in the cortex of the painted turtle, and large elevations in [Ca(2+)](c), severe E(m) depolarization and ECD are avoided. DORs are expressed in high quantity throughout the turtle brain relative to the mammalian brain; however, the role of DORs in anoxic NMDAR regulation has not been investigated in turtles. We examined the effect of DOR blockade with naltrindole (1-10 micromol l(-1)) on E(m), NMDAR activity and [Ca(2+)](c) homeostasis in turtle cortical neurons during normoxia and the transition to anoxia. Naltrindole potentiated normoxic NMDAR currents by 78+/-5% and increased [Ca(2+)](c) by 13+/-4%. Anoxic neurons treated with naltrindole were strongly depolarized, NMDAR currents were potentiated by 70+/-15%, and [Ca(2+)](c) increased 5-fold compared with anoxic controls. Following naltrindole washout, E(m) remained depolarized and [Ca(2+)](c) became further elevated in all neurons. The naltrindole-mediated depolarization and increased [Ca(2+)](c) were prevented by NMDAR antagonism or by perfusion of the G(i) protein agonist mastoparan-7, which also reversed the naltrindole-mediated potentiation of NMDAR currents. Together, these data suggest that DORs mediate NMDAR activity in a G(i)-dependent manner and prevent deleterious NMDAR-mediated [Ca(2+)](c) influx during anoxic insults in the turtle cortex.
AuthorsMatthew E Pamenter, Leslie T Buck
JournalThe Journal of experimental biology (J Exp Biol) Vol. 211 Issue Pt 21 Pg. 3512-7 (Nov 2008) ISSN: 0022-0949 [Print] England
PMID18931323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Intercellular Signaling Peptides and Proteins
  • Mas7 protein, synthetic
  • Neurotoxins
  • Peptides
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, delta
  • Naltrexone
  • naltrindole
  • Calcium
Topics
  • Animals
  • Calcium (metabolism)
  • Cells, Cultured
  • Cerebral Cortex (physiology)
  • Electrophysiology
  • Homeostasis
  • Hypoxia, Brain (metabolism)
  • In Vitro Techniques
  • Intercellular Signaling Peptides and Proteins
  • Naltrexone (analogs & derivatives, pharmacology)
  • Neurons (drug effects, metabolism)
  • Neurotoxins (pharmacology)
  • Patch-Clamp Techniques
  • Peptides (pharmacology)
  • Receptors, N-Methyl-D-Aspartate (drug effects, metabolism)
  • Receptors, Opioid, delta (drug effects, metabolism)
  • Turtles (metabolism)

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