Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Oct 5

PMID 20889977

Citations 32

Authors

Hiroko Ikeda

Mayumi Miyatake

Noriaki Koshikawa

Kuniyasu Ochiai

Kiyoshi Yamada

Alexi Kiss

Maureen J Donlin

W Michael Panneton

James D Churchill

Michael Green

Akbar M Siddiqui

Andrew L Leinweber

Nicholas R Crews

Lubov A Ezerskiy

Victoria R Rendell

Mariana M Belcheva

Carmine J Coscia

Affiliations

Soon will be listed here.

Abstract

Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple μ opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by μ opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGFβ1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of μ opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.

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