Circadian machinery regulating diurnal exacerbation of neuropathic pain hypersensitivity

　Pain hypersensitivity is often caused by peripheral nerve injury, which is associated with the hyperexcitability of neurons in the dorsal horn of the spinal cord. Extracellular ATP in the spinal cord has been implicated in the development and maintenance of neuropathic pain hypersensitivity. Diurnal alterations in pain hypersensitivity have been confirmed in patients with chronic pain disorders such as cancer, rheumatoid arthritis, diabetic neuropathy, fibromyalgia, and multiple sclerosis; however, the underlying mechanism remains unknown. In the present study, we clarified the underlying mechanism of diurnal exacerbation of neuropathic pain hypersensitivity.
　The secretion of glucocorticoids from the adrenal glands exhibits diurnal variation. We investigated whether the diurnal secretion of glucocorticoids affects the pain intensity of peripheral nerve-injured mice. Temporal elevations in glucocorticoids levels enhance the extracellular release of ATP in the spinal cord, which stimulates purinergic receptors on microglia in the dorsal horn. The stimuli of purinergic receptors exacerbate the neuropathic pain hypersensitivity.

Researcher’s comments: Our present findings reveal an uncovered circadian machinery affecting pain hypersensitivity caused by peripheral nerve injury and also provide novel approaches to the management of chronic pain.

For more information about this research, see Nature Comminications, Koyanagi and Ohdo et al.: “Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia”DOI: 10.1038/NCOMMS13102

Schematic diagram indicating the mechanism of diurnal exacerbation of neuropathic pain hypersensitivity