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The Journal of Neuroscience, January 12, 2005, 25(2):430-435; doi:10.1523/JNEUROSCI.3170-04.2005

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Morphine-Induced Chemotaxis and Brain-Derived Neurotrophic Factor Expression in Microglia

Naoko Takayama and Hiroshi Ueda

Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan

The addition of morphine at 1 µM induced morphological changes of cultured microglia such that they changed from having globular or bipolar rod-like shapes to being flat and lamellipodial, with membrane ruffling at the edge, which was stained with phalloidin. The membrane ruffling was clearly colocalized with Rac. Morphine also induced chemotaxis in Boyden chamber analysis at concentrations of 1 µM or more in microglia and the microglial cell line EOC 2. All of these changes were abolishable by naloxone, antisense oligodeoxynucleotide for µ-opioid receptor (MOR), pertussis toxin (PTx), and wortmannin, but not genistein or 1,10-phenanthroline. The addition of morphine to microglia stimulated the gene expression of brain-derived neurotrophic factor (BDNF) as early as the 1 hr point, and this lasted for >12 hr. Morphine induced BDNF gene expression and ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation, and these were abolishable by naloxone, wortmannin, PD98059, genistein, and 1,10-phenanthroline. The addition of conditioned medium derived from the culture of morphine-treated microglia also increased the phosphorylation of ERK1/2. All of these findings suggest that morphine induces significant changes in both morphology and gene expression at relatively high concentrations, but the underlying signaling pathways downstream of MOR and G_i/o appear to be different from each other. Phosphoinositide 3-kinase activation and Rac activation are involved in chemotaxis, whereas indirect pathways through ERK1/2 phosphorylation induced by unknown growth factors generated through an MOR-mediated metalloprotease activation are linked to the enhanced BDNF gene expression.

Key words: membrane ruffling; Rac; EOC 2; phosphoinositide 3-kinase ; PI3K; metalloprotease; transactivation

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Received Aug 3, 2004; revised November 18, 2004; accepted November 23, 2004.

This article has been cited by other articles:

				M. Ifuku, K. Farber, Y. Okuno, Y. Yamakawa, T. Miyamoto, C. Nolte, V. F. Merrino, S. Kita, T. Iwamoto, I. Komuro, et al. Bradykinin-Induced Microglial Migration Mediated by B1-Bradykinin Receptors Depends on Ca2+ Influx via Reverse-Mode Activity of the Na+/Ca2+ Exchanger J. Neurosci., November 28, 2007; 27(48): 13065 - 13073. [Abstract] [Full Text] [PDF]

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