Programmed Cell Death Ligand 1 Is Essential for Electroacupuncture-Mediated Analgesia in the Cerebellum of Fibromyalgia Mice

<b>Background:</b> Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both for individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand 1 (PD-L1)/PD-1 were first identified to be involved in cancer immunotherapy, and their application to pain management has not been yet investigated. <b>Methods:</b> In this study, we aimed to explore the mechanism underlying the action of PD-L1 on the PD-1 pathway in a mouse model of fibromyalgia. <b>Results:</b> We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, <i>n</i> = 9) and thermal (D4: 4.28 ± 0.21 s, <i>n</i> = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, and <i>transient receptor potential vanilloid 1</i> (<i>Trpv1</i>) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and <i>Trpv1</i> knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1-neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. <b>Conclusions:</b> Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia management.