Mitochondrial ERK plays a key role in δ-opioid receptor neuroprotection against acute mitochondrial dysfunction

Neurochem Int. 2011 Nov;59(6):739-48. doi: 10.1016/j.neuint.2011.08.005. Epub 2011 Aug 12.


It is well established that stimulating delta-opioid receptor (DOR) with its specific agonists elicits neuroprotection against hypoxia/ischemia. Mitochondrial dysfunction plays a key role in hypoxic neuronal injury, but the effects of DOR activation on mitochondrial dysfunction in neurons are poorly elucidated. In this investigation, we studied the effects of [D-Ala2, D-Leu5] enkephalin (DADLE), a potent DOR agonist, on acute mitochondrial dysfunction and ensuing cell damage induced by sodium azide in primary rat cortical neuronal cultures, and explored possible mechanisms underlying. Here, we show that DADLE reverses NaN(3)-induced acute mitochondrial dysfunction by selectively activating DOR, mainly including mitochondrial membrane depolarization, mitochondrial Ca(2+) overload and reactive oxygen species generation. DOR stimulation also inhibits cytochrome c release and caspase-3 activation, and attenuates neuronal death caused by acute NaN(3) insults. Furthermore, DOR activation with DADLE protects neurons from acute NaN(3) insults mainly through PKC-ERK pathway, and mitochondrial ERK activation is especially required for DOR neuroprotection against acute mitochondrial dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cytoprotection / drug effects
  • Cytoprotection / physiology*
  • Enkephalin, Leucine-2-Alanine / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / enzymology*
  • Mitochondrial Diseases / metabolism*
  • Mitogen-Activated Protein Kinase 3 / physiology*
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / metabolism
  • Primary Cell Culture
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / physiology
  • Sodium Azide / toxicity
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Analgesics, Opioid
  • Receptors, Opioid, delta
  • Enkephalin, Leucine-2-Alanine
  • Sodium Azide
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases