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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