Spinal p38 MAPK/PGC-1α/SIRT3 signaling pathway mediates remifentanil-induced hyperalgesia in rats via ROS release and NR2B activation.

Remifentanil-induced hyperalgesia (RIH) poses a significant clinical challenge. Our research group has previously confirmed that abnormal activation of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal dorsal horn contributes to RIH, but the specific regulatory pathway remains unclear. It is known that p38 MAPK can regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and the PGC-1α/Sirtuin 3 (SIRT3) pathway plays an important role in various pain models. However, whether this pathway is involved in RIH remains to be elucidated. In this study, an RIH model was established using male Sprague-Dawley (SD) rats, and significant hyperalgesia was observed in the RIH group. Intrathecal injection of the p38 MAPK inhibitor SB203580 or the PGC-1α agonist ZLN005 significantly alleviated this hyperalgesic response. Mechanistic analysis further revealed that in the RIH model group, activation of p38 MAPK was increased in spinal dorsal horn microglia, while the expression of PGC-1α and SIRT3 were decreased. In neurons, reactive oxygen species (ROS) levels were increased, accompanied by increased expression of the N-methyl-d-aspartate receptor (NMDAR) subunit NR2B, synaptic structural remodeling, and an increase in the amplitude and frequency of NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs). All these pathological changes could be reversed by intervention with either SB203580 or ZLN005. In conclusion, this study demonstrates that remifentanil activates p38 MAPK in spinal dorsal horn microglia, inhibits the PGC-1α/SIRT3 signaling pathway, promotes ROS release, subsequently activates the neuronal NR2B subunit, and ultimately induces RIH. This mechanism provides a new potential target for the treatment of RIH.