title: Microglia activation precedes the anti-opioid BDNF and NMDA receptor mechanisms underlying morphine analgesic tolerance.
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.
authors: Yosuke
authors: Y
authors: Matsushita
authors: Idowu O
authors: IO
authors: Omotuyi
authors: Takehiro
authors: T
authors: Mukae
authors: Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp.
authors: Hiroshi
authors: H
authors: Ueda
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009020:Morphine / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine