Neuroprotective role of delta-opioid receptors in cortical neurons

Am J Physiol Cell Physiol. 2002 Jun;282(6):C1225-34. doi: 10.1152/ajpcell.00226.2001.

Abstract

We recently demonstrated that delta-opioid receptor (DOR) activation protects cortical neurons against glutamate-induced injury. Because glutamate is a mediator of hypoxic injury in neurons, we hypothesized that DOR is involved in neuroprotection during O2 deprivation and that its activation/inhibition may alter neuronal susceptibility to hypoxic stress. In this work, we tested the effect of opioid receptor activation and inhibition on cultured cortical neurons in hypoxia (1% O2). Cell injury was assessed by lactate dehydrogenase release, morphology-based quantification, and live/dead staining. Our results show that 1) immature neurons (days 4 and 6) were not significantly injured by hypoxia until 72 h of exposure, whereas day 8 neurons were injured after only 24-h hypoxia; 2) DOR inhibition (naltrindole) caused neuronal injury in both day 4 and day 8 normoxic cultures and further augmented hypoxic injury in these neurons; 3) DOR activation ([D-Ala2,D-Leu5]enkephalin) reduced neuronal injury in day 8 cultures after 24 h of normoxic or hypoxic exposure and attenuated naltrindole-induced injury with prolonged exposure; and 4) mu- or kappa-opioid receptor inhibition (beta-funaltrexamine or nor-binaltorphimine) had little effect on neurons in either normoxic or hypoxic conditions. Collectively, these data suggest that DOR plays a crucial role in neuroprotection in normoxic and hypoxic environments.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Count
  • Cell Differentiation / physiology
  • Cell Hypoxia / physiology*
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Enkephalin, Leucine-2-Alanine / pharmacology
  • Hypoxia, Brain / metabolism*
  • L-Lactate Dehydrogenase / metabolism
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / metabolism*
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Time Factors

Substances

  • Narcotic Antagonists
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Naltrexone
  • Enkephalin, Leucine-2-Alanine
  • L-Lactate Dehydrogenase
  • naltrindole