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

Purpose: 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