Stimulation of nuclear receptor REV-ERBs suppresses inflammatory responses in spinal microglia.

As spinal microglia have a critical role in the development of chronic pain, regulation of their activity is essential for pain relief. Previous study has shown that stimulation of the REV-ERB nuclear receptors in the spinal dorsal horn produces antinociception in animal models of both inflammatory and neuropathic pain. However, the involvement of spinal microglia in the antinociceptive action of REV-ERBs remains to be elucidated.

Stimulation of nuclear receptor REV-ERBs suppresses production of pronociceptive molecules in cultured spinal astrocytes and ameliorates mechanical hypersensitivity of inflammatory and neuropathic pain of mice.

The orphan nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammatory-related gene transcription in astroglioma cells, but their role in nociceptive transduction has yet to be elaborated. Spinal dorsal horn astrocytes contribute to the maintenance of chronic pain. Treatment of cultured spinal astrocytes with specific REV-ERBs agonists SR9009 or GSK4112 significantly prevented lipopolysaccharide (LPS)-induced mRNA upregulation of pronociceptive molecules interleukin-1β (IL-1β) mRNA, interleukin-6 (IL-6) mRNA and matrix metalloprotease-9 (MMP-9) mRNA, but not CCL2 mRNA expression.