Role of Delta-Opioid Receptor Function in Neurogenesis and Neuroprotection

J Neurochem. 2006 Jun;97(5):1494-505. doi: 10.1111/j.1471-4159.2006.03849.x.

Abstract

The present study was undertaken to evaluate the implication of delta-opioid receptor function in neurogenesis and neuroprotection. We found that the stimulation of delta-opioid receptors by the selective delta-opioid receptor agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (10 nm) promoted neural differentiation from multipotent neural stem cells obtained from embryonic C3H mouse forebrains. In contrast, either a selective micro-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), or a specific kappa-opioid receptor agonist, (-)-trans-(1S,2S)-U-50488 hydrochloride (U50,488H), had no such effect. In addition to neural differentiation, the increase in cleaved caspase 3-like immunoreactivity induced by H2O2 (3 microm) was suppressed by treatment with SNC80 in cortical neuron/glia co-cultures. These effects of SNC80 were abolished by a Trk-dependent tyrosine kinase inhibitor: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one (K-252a). The SNC80-induced neural differentiation was also inhibited by treatment with the protein kinase C (PKC) inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitor, mitogen-activated protein kinase kinase (MEK) inhibitor or Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These findings raise the possibility that delta-opioid receptors play a crucial role in neurogenesis and neuroprotection, mainly through the activation of Trk-dependent tyrosine kinase, which could be linked to PI3K, PKC, CaMKII and MEK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Benzamides / pharmacology
  • Brain / cytology
  • Brain / embryology
  • Brain / growth & development
  • Brain-Derived Neurotrophic Factor / metabolism
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Proliferation / drug effects*
  • Coculture Techniques
  • Cytoprotection / drug effects
  • Cytoprotection / physiology*
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Mice, Inbred C3H
  • Narcotics / pharmacology
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Piperazines / pharmacology
  • Receptor, trkA / drug effects
  • Receptor, trkA / metabolism
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, delta / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*

Substances

  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Narcotics
  • Piperazines
  • Receptors, Opioid, delta
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Receptor, trkA
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases