Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia

Satoru Koyanagi,Naoki Kusunose,Takahiro Akamine,Shigehiro Ohdo,Kazuhide Inoue,Marie Taniguchi,Yuki Kanado,Makoto Tsuda,Michael W Salter,Yuta Kohro,Takahiro Masuda,Yui Ozono,Naoya Matsunaga

doi:10.1038/ncomms13102

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.

Highlights

Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but the underlying mechanisms are enigmatic
Since the glucocorticoid receptor (GCR) is expressed in most cell types, including spinal neurons, microglia and astrocytes[23,24,25], we investigated whether the diurnal secretion of adrenal glucocorticoids affects the threshold of mechanical allodynia in peripheral nerve-injured mice
To determine the pathological relevance of the diurnal secretion of adrenal glucocorticoids in neuropathic hypersensitivity, we investigated the influence of adrenalectomy on the threshold of mechanical allodynia in nerve-injured mice

Summary

Introduction

Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but the underlying mechanisms are enigmatic. 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. Our findings reveal an unappreciated circadian machinery affecting pain hypersensitivity caused by peripheral nerve injury, opening up novel approaches to the management of chronic pain. Since the glucocorticoid receptor (GCR) is expressed in most cell types, including spinal neurons, microglia and astrocytes[23,24,25], we investigated whether the diurnal secretion of adrenal glucocorticoids affects the threshold of mechanical allodynia in peripheral nerve-injured mice. Temporal elevations in glucocorticoid levels enhance the extracellular release of ATP in the spinal cord, which stimulates purinergic receptors on microglia in the dorsal horn. Our findings reveal an underlying mechanism of diurnal exacerbation of neuropathic mechanical allodynia and provide novel approaches to the management of chronic pain

Methods

Results

Conclusion