title: Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia.
abstract: Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but the underlying mechanisms are enigmatic. Here, we report that mechanical pain hypersensitivity in sciatic nerve-injured mice shows pronounced diurnal alterations, which critically depend on diurnal variations in glucocorticoids from the adrenal glands. Diurnal enhancement of pain hypersensitivity is mediated by glucocorticoid-induced enhancement of the extracellular release of ATP in the spinal cord, which stimulates purinergic receptors on microglia in the dorsal horn. We identify serum- and glucocorticoid-inducible kinase-1 (SGK-1) as the key molecule responsible for the glucocorticoid-enhanced release of ATP from astrocytes. SGK-1 protein levels in spinal astrocytes are increased in response to glucocorticoid stimuli and enhanced ATP release by opening the pannexin-1 hemichannels. Our findings reveal an unappreciated circadian machinery affecting pain hypersensitivity caused by peripheral nerve injury, thus opening up novel approaches to the management of chronic pain.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Glocal Healthcare, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Marie
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Akamine
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kanado
authors.affiliation: Department of Molecular and System Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Ozono
authors.affiliation: Department of Life Innovation, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Life Innovation, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kohro
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Glocal Healthcare, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Department of Life Innovation, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada M5T 1P8.
authors.forename: Michael W
authors.identifier: http://orcid.org/0000-0001-6897-6585
authors.initials: MW
authors.lastname: Salter
authors.affiliation: Department of Molecular and System Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000315:Adrenalectomy; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000097:blood / Q000494:pharmacology*; D006930:Hyperalgesia / Q000503:physiopathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008297:Male; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000255:Adenosine Triphosphate; D003345:Corticosterone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases