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.
Current Pharmaceutical Design
Title:Microglia Activation Precedes the Anti-Opioid BDNF and NMDA Receptor Mechanisms Underlying Morphine Analgesic Tolerance
Volume: 19 Issue: 42
Author(s): Yosuke Matsushita, Idowu O. Omotuyi, Takehiro Mukae and Hiroshi Ueda
Affiliation:
Keywords: Microglia, brain-derived neurotrophic factor, NMDA receptor, morphine tolerance, anti-opioid mechanism.
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.
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Matsushita Yosuke, Omotuyi O. Idowu, Mukae Takehiro and Ueda Hiroshi, Microglia Activation Precedes the Anti-Opioid BDNF and NMDA Receptor Mechanisms Underlying Morphine Analgesic Tolerance, Current Pharmaceutical Design 2013; 19 (42) . https://dx.doi.org/10.2174/138161281942140105161733
DOI https://dx.doi.org/10.2174/138161281942140105161733 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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