title: BK channels in microglia are required for morphine-induced hyperalgesia.
abstract: Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance.
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Morinaga
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, National Defense Medical College, Tokorozawa 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Physiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Meredith
authors.affiliation: Department of Molecular and Cellular Anatomy, Faculty of Health Promotional Sciences, Tokoha University, Hamamatsu, Shizuoka 431-2102, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1, Otemachi, Chiyoda-ku, Tokyo 100-004, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1, Otemachi, Chiyoda-ku, Tokyo 100-004, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004361:Drug Tolerance; D020868:Gene Silencing; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D009154:Mutation; D009474:Neurons; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement; D010455:Peptides / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D010455:Peptides; D017450:Receptors, Opioid, mu; D058848:Receptors, Purinergic P2X4; D016718:Arachidonic Acid; D009020:Morphine; C064719:iberiotoxin