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.

Stimulus‐dependent modifications in astrocyte‐derived extracellular vesicle cargo regulate neuronal excitability

“…ATP is a potent inducer of EV shedding in several cell types, including microglia and astrocytes (Bianco et al, 2005(Bianco et al, , 2009Takenouchi et al, 2015). In brain, ATP can be co-released from neurons with other neurotransmitters (Edwards, Gibb, & Colquhoun, 1992;Silinsky, Gerzanich, & Vanner, 1992;Sperlagh, Kittel, Lajtha, & Vizi, 1995), and from astrocytes in response to glutamate, mechanical stretch, activation of toll-like receptor 3, and glucocorticoids (Beckel et al, 2018;Guthrie et al, 1999;Koyanagi et al, 2016;Queiroz, Gebicke-Haerter, Schobert, Starke, & von Kügelgen, 1997;Xiong et al, 2018). Extracellular ATP signals by binding to P2 receptors that include ionotropic P2X (P2X1−7) and metabotropic P2Y receptors (P2Y1, 2, 4, 6, 11-14;reviewed in Burnstock, 2007).…”

Emerging relevance of circadian rhythms in headaches and neuropathic pain

“…Indeed, when the sciatic nerve is surgically ligated, rats and mice have increased pain sensitivity during the day. 153,154 Pain rhythmicity in other experimental models 155,156 remains to be investigated.…”

“…[159][160][161] In the aforementioned studies of sciatic nerve injury, adenovirusmediated alteration in the NR2B-CREB-CRTC1 signalling pathway was shown to improve pain behaviour, 153 whereas glucocorticoid-induced ATP release from spinal astrocytes aggravates daily hypersensitivity. 154 Changes in the circadian expression of melatonin receptors in the hypothalamus were observed in rodents after peripheral nerve injuries, suggesting a possible role of the central clock. 162 Pioneering studies have further provided molecular evidence that core circadian genes may play an important role in pain.…”

Circadian control of pain and neuroinflammation

“…Expression of cytokines such as IL‐6 and CCL2 by cultured spinal astrocytes is increased by a knockdown of the PER1 gene (Sugimoto et al, ). These spinal astrocytes, which become activated following peripheral nerve injury and other peripheral and CNS injuries, were also recently found to control mechanical hypersensitivity through the release of ATP, mediated by glucocorticoids by inducing the expression of serum‐ and glucocorticoid‐inducible kinase 1 (Koyanagi et al, ). Many studies have investigated the release of ATP by astrocytes, which in fact shows a circadian oscillation (Marpegan et al, ; Womac, Burkeen, Neuendorff, Earnest, & Zoran, ) that is regulated by mitochondrial calcium (Burkeen, Womac, Earnest, & Zoran, ).…”

“…Given the close association between the immune system and injury, it is plausible that there is also a link between the circadian rhythm of the immune system and the circadian rhythm of NP. For example, it is known that after injury, there is an increased activation of astrocytes and microglia within the CNS, as well as an upregulation of proinflammatory mediators, cytokines, and chemokines (Ji, Samad, Jin, Schmoll, & Woolf, ; Kawasaki, Xu, et al, ; Kawasaki, Zhang, Cheng, & Ji, ; Koyanagi et al, ) and an increase in immune cells such as macrophages, neutrophils, and T cells (Ellis & Bennett, ). These factors contribute to the perception of pain, and they all have been demonstrated to display circadian rhythms themselves (Fortier et al, ; Gibbs et al, , ; Hayashi, Shimba, & Tezuka, ; Keller et al, ; Wei, Heaton, Morris, & Harrison, ).…”