Downregulation of Mfn2 Contributes to Chronic Postsurgical Pain via Inducing the Pyroptosis of GABAergic Neurons in the Spinal Cord.

BACKGROUND

Chronic postoperative pain (CPSP) is a significant public health issue due to the complex pathophysiological mechanism. Existing evidence has pointed out that the loss of gamma-aminobutyric acid-ergic (GABAergic) neurons played a critical role in various neuropathic pain models. Previous studies also found that pyroptosis-mediated neuroinflammation was involved in neuropathological pain. However, it remains unclear what the relationship is between pyroptosis and the loss of spinal GABAergic neurons in CPSP. This study aimed to investigate the role and mechanism of GABAergic neuron pyroptosis in CPSP.

METHODS

We used skin/muscle incision and retraction (SMIR) to establish the CPSP model in rats. Mechanical allodynia was assessed using the Von Frey test. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the role and mechanism of GABAergic neuron pyroptosis during CPSP.

RESULTS

We observed the pyroptosis of GABAergic neurons in the spinal cord following SMIR. Intrathecal administration of the GSDMD inhibitor decreased the pyroptosis of GABAergic neurons in the spinal cord and reversed SMIR-induced mechanical allodynia. In addition, we found that SMIR induced a significant decrease in the level of Mfn2 in the neurons, accompanied by mitochondrial dysfunction and reactive oxygen species (ROS) accumulation in SMIR rats. Intrathecal injection of the Mfn2 activator reduced mitochondrial dysfunction and ROS, alleviated the pyroptosis of GABAergic neurons in the spinal cord, which alleviated the SMIR-induced mechanical allodynia.

CONCLUSIONS

Our study demonstrated that downregulation of Mfn2 leads to mitochondrial dysfunction and ROS accumulation, which promotes the pyroptosis of spinal GABAergic neurons and the development of chronic pain.