Open AccessGlucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia
Author(s) -
Satoru Koyanagi,
Katsuhiko Naoki,
Marie Taniguchi,
Takuya Akamine,
Yuki Kanado,
Yui Ozono,
Takahiro Masuda,
Yuta Kohro,
Naoya Matsumoto,
Makoto Tsuda,
Michael W. Salter,
Kazuhide Inoue,
Shigehiro Ohdo
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13102
Subject(s) - purinergic receptor , glucocorticoid , neuropathic pain , microglia , medicine , spinal cord , glucocorticoid receptor , allodynia , sciatic nerve , endocrinology , extracellular , chronic pain , nociception , neuroscience , anesthesia , hyperalgesia , inflammation , biology , receptor , adenosine , microbiology and biotechnology
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.