Microglia Activation Precedes the Anti-Opioid BDNF and NMDA Receptor Mechanisms Underlying Morphine Analgesic Tolerance

Author(s): Yosuke Matsushita , Idowu O. Omotuyi , Takehiro Mukae , Hiroshi Ueda .

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 42 , 2013

Abstract:

Herein, we investigated the role of periaqueductal gray (PAG)-resident microglia in the development of morphine tolerance and its underlying mechanisms. We showed that clodronate and minocycline known as microglia inhibitors reversed morphine tolerance, providing proof that microglia activation has key role in the development of morphine tolerance. The microglia-mediated anti-opioid mechanism occurs via sequential BDNF release and NMDA expression. Experimental evidence is provided here as conditional bdnf knockout mice (bdnf-/-) failed to develop tolerance following Cre-recombinase adenovirus treatment. Increased BDNF expression followed microglia activation in acute minocycline treatment reversible manner. Following BDNF release, NR2A subunit of NMDA receptor was upregulated in anti-BDNF reversible manner showing the contribution of BDNF signaling in the control of NMDA receptor expression following chronic morphine treatment. Our data provide compelling evidence that microglia activation and BDNF release are key regulators in opioid tolerance mechanism via glutaminergic synapse plasticity.

Keywords: Microglia, brain-derived neurotrophic factor, NMDA receptor, morphine tolerance, anti-opioid mechanism.

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Article Details

VOLUME: 19
ISSUE: 42
Year: 2013
Page: [7355 - 7361]
Pages: 7
DOI: 10.2174/138161281942140105161733
Price: $58

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