TMEM251 loss-induced autophagy dysfunction in the anterior cingulate cortex contributes to chronic postoperative pain

Macroautophagy/autophagy plays a crucial role in maintaining nervous system homeostasis but its role in chronic postoperative pain (CPOP) remains poorly understood. Here, we identify impaired autophagy and the accumulation of synaptic proteins in the anterior cingulate cortex (ACC) during the maintenance of CPOP after skin/muscle incision and retraction (SMIR). Lysosomal hydrolase levels are reduced upon SMIR, accompanied by a deficiency of the lysosomal trafficking protein transmembrane protein 251 (TMEM251, also named LYSET). TMEM251 overexpression alleviates impaired autophagy, accumulation of synaptic proteins within autophagy substrates, and maintenance of CPOP in SMIR mice. Conversely, TMEM251 knockdown induces autophagy impairment, accumulation of synaptic proteins, and chronic pain phenotypes in naive mice. Autophagy dysfunction is most pronounced in CaMKIIα-positive neurons in the ACC post-surgery, resulting in their activation, which is mitigated by TMEM251 overexpression. Chemogenetic activation of CaMKIIα neurons exacerbates autophagy impairment and CPOP, while their inhibition rescues SMIR-induced autophagy and pain phenotypes. Taken together, our study highlights the close relationship between impaired autophagy and neuronal activation in the promotion of chronic postoperative pain.