STING Modulating ER-Phagy in the Prelimbic Cortex Neurons Contributed to Neuropathic Pain and Emotional Comorbidity

Our previous data suggested that autophagy is crucial for neuropathic pain. The different cell types and varying degrees of regulation of STING may lead to a paradoxical effect on pain and emotions in the neuropathic pain model. Up to now, whether STING modulates neuropathic pain in PrL neurons via ER-phagy is still unknown.

In this study, we investigated the effect of ER-phagy in the prefrontal cortex (PrL) on neuropathic pain. We administered 4-phenylbutyric acid, tunicamycin, 3-methyladenine, and rapamycin to evaluate the interaction between endoplasmic reticulum (ER) stress and autophagy in the PrL of SNL (spinal nerve ligation). We injected AAV to investigate whether ER-phagy modulated pain and emotional behaviors. We further explored whether STING and its pathway as a modulation target for ER-phagy to participate in the pain process. We injected 2'3-cGAMP and RU521 to modulate the cGAS/STING pathway in ER-phagy in SNL mice. Moreover, we modulated STING expression and regulated the levels of ER-phagy and the interaction between STING and LC3 in neurons through PrL AAV injections.

The data indicated that ER-phagy alleviated the excessive ER stress induced by SNL in PrL through the cGAS/STING pathway. Regulating ER-phagy in PrL neurons through AAV tools altered pain and emotion-related behaviors. In addition, regulating STING in PrL neurons altered the comorbidity of pain and emotion. Importantly, the binding interaction between STING and LC3 in PrL neurons provides a novel target for PrL ER-phagy.

Enhanced ER-phagy of PrL neurons provides analgesic, anti-anxiety, and antidepressant effects through modulating STING in SNL mice.