Inhibition of Nuclear Receptor Related Orphan Receptor γ Ameliorates Mechanical Hypersensitivity Through the Suppression of Spinal Microglial Activation.

Microglia are crucial in induction of central sensitization under a chronic pain state. Therefore, control of microglial activity is important to ameliorate nociceptive hypersensitivity. The nuclear receptor retinoic acid related orphan receptor γ (RORγ) contributes to the regulation of inflammation-related gene transcription in some immune cells, including T cells and macrophages. Their role and function in regulation of microglial activity and nociceptive transduction have yet to be elaborated. Treatment of cultured microglia with specific RORγ inverse agonists, SR2211 or GSK2981278, significantly suppressed lipopolysaccharide (LPS)-induced mRNA expression of pronociceptive molecules interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Intrathecal treatment of naïve male mice with LPS markedly induced mechanical hypersensitivity and upregulation of ionized calcium-biding adaptor molecule (Iba1) in the spinal dorsal horn, indicating microglial activation. In addition, intrathecal treatment with LPS significantly induced mRNA upregulation of IL-1ß and IL-6 in the spinal dorsal horn. These responses were prevented by intrathecal pretreatment with SR2211. In addition, intrathecal administration of SR2211 significantly ameliorated established mechanical hypersensitivity and upregulation of Iba1 immunoreactivity in the spinal dorsal horn of male mice following peripheral sciatic nerve injury. The current findings demonstrate that blockade of RORγ in spinal microglia exerts anti-inflammatory effects, and that RORγ may be an appropriate target for the treatment of chronic pain.

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. In the current study, we found that intrathecal treatment with the REV-ERB agonist SR9009 significantly blocked the increase in ionized calcium-binding adaptor molecule immunoreactivity in the spinal dorsal horn of mice following intrathecal administration of lipopolysaccharide and peripheral sciatic nerve ligation. Furthermore, both Rev-erbα and Rev-erbß mRNAs were expressed in cultured rat spinal microglia. Treatment of cultured rat spinal microglia with SR9009 significantly blocked the lipopolysaccharide-induced increase in interleukin (IL)-1ß and IL-6 mRNA expression. In conclusion, the current findings suggest that REV-ERBs negatively regulate spinal microglial activity and might contribute to the REV-ERB-mediated antinociceptive effect in the spinal dorsal horn.