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Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse

Hiroko Ikeda1, Mayumi Miyatake, Noriaki Koshikawa

  • 1E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, Missouri 63104, USA.

The Journal of Biological Chemistry
|October 5, 2010
PubMed

Insights

Chronic opioid exposure reduces thrombospondin 1 (TSP1) in astrocytes, impacting neurite outgrowth and synapse formation via μ opioid receptor and ERK signaling pathways. This suggests opiates may inhibit neural development.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Opioid receptors and epidermal growth factor receptor (EGFR) signaling pathways, including ERK/MAPK phosphorylation, mediate cell-specific responses.
  • Astrocytes exhibit multiple, temporally distinct mechanisms for μ opioid receptor-mediated ERK activation.
  • Thrombospondin 1 (TSP1), synthesized by astrocytes, plays a role in synapse formation and neurite outgrowth.

Purpose of the Study:

  • To investigate the mechanism by which chronic opiate treatment down-regulates thrombospondin 1 (TSP1) expression in astrocytes.
  • To elucidate the role of TSP1 in opioid-induced modulation of astrocyte signaling and neuronal development.

Main Methods:

  • Investigated TSP1 levels in astrocytes following acute and chronic morphine treatment in rats.
  • Examined the involvement of μ opioid receptor and ERK-dependent mechanisms in morphine's effect on TSP1.
  • Utilized astrocyte-neuron co-cultures to assess the impact of morphine on neurite outgrowth and synapse formation.
  • Employed function-blocking TSP1 antibodies to probe acute morphine signaling pathways.

Main Results:

  • Chronic opioids repressed TSP1 gene expression and reduced protein levels in astrocytes via μ opioid receptor and ERK-dependent pathways.
  • Morphine depleted TSP1 levels stimulated by TGFβ1 and abolished subsequent ERK activation.
  • Acute and chronic morphine treatments inhibited neurite outgrowth and synapse formation in astrocyte-neuron co-cultures.
  • Evidence suggests acute morphine may utilize TSP1 as a source of EGF-like ligands to activate EGFR.

Conclusions:

  • Chronic opioid administration significantly impacts astrocyte TSP1 expression, affecting neuronal development.
  • Morphine's inhibitory effects on neurite outgrowth and synapse formation are linked to TSP1 modulation.
  • Opioid-induced alterations in EGFR transactivation pathways, involving TSP1, may underlie diminished neural plasticity.

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