Intrathecal EP4 Antagonist Alleviates Neuronal and Glial Activation and Hyperalgesia in a Mouse Model of Endometriosis

Peiya Fan,1– 3,* Wei Xiong,4,* Yixiao Chen,1,2,* Yunjing Bai,1,2 Tian Li1,21Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China; 4Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tian Li, Email [email protected]: Endometriosis-associated pain presents a significant clinical challenge due to its complex nature, often manifesting as mixed pain types and hyperalgesia, with current treatments offering limited relief. Previous studies have mostly focused on the mechanisms of peripheral lesions in endometriosis, while research on the regulatory role of the central nervous system in the development and progression of endometriosis-associated chronic pain remains scarce. This study explores the therapeutic potential of an EP4 antagonist (E7046) in a mouse model of endometriosis-induced hyperalgesia.Methods: Daily intrathecal administration of E7046 was performed, and pain thresholds were measured at various intervals. Neuronal and glial activation in the spinal cord were assessed using immunofluorescence and Nissl staining techniques.Results: EP4 antagonist (E7046) treatment reduced hyperalgesia and lowered pro-inflammatory cytokine levels by 30– 40% relative to saline-treated endometriosis mice (n = 4 per group). Further, a reduction in neuronal and glial cell activation in the spinal cord was observed, suggesting decreased spinal inflammation and neuronal sensitization.Discussion: These findings indicate that the EP4 antagonist effectively mitigates endometriosis-induced hyperalgesia by inhibiting neural and glial activation. E7046 may confer beneficial effects against endometriosis-related pain in this preclinical animal model, and further mechanistic and translational studies are still needed.Keywords: endometriosis, chronic pain, microglia, EP4 receptor