title: Morphine modulation of thrombospondin levels in astrocytes and its implications for neurite outgrowth and synapse formation.
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.
authors.affiliation: E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, Missouri 63104, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Mayumi
authors.initials: M
authors.lastname: Miyatake
authors.forename: Noriaki
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamada
authors.forename: Alexi
authors.initials: A
authors.lastname: Kiss
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Donlin
authors.forename: W Michael
authors.initials: WM
authors.lastname: Panneton
authors.forename: James D
authors.initials: JD
authors.lastname: Churchill
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.forename: Akbar M
authors.initials: AM
authors.lastname: Siddiqui
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Leinweber
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Crews
authors.forename: Lubov A
authors.initials: LA
authors.lastname: Ezerskiy
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Rendell
authors.forename: Mariana M
authors.initials: MM
authors.lastname: Belcheva
authors.forename: Carmine J
authors.initials: CJ
authors.lastname: Coscia
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D016501:Neurites / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D009294:Narcotics; D017450:Receptors, Opioid, mu; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D009020:Morphine; C483803:Egfr protein, rat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases