Late-pregnancy oxytocin alleviates neuroinflammation and hyperalgesia in chronic migraine model via PVN to NTS oxytocinergic projections and ECM-receptor interaction signaling.

Migraine is a primary neurological disorder characterized by recurrent episodes of headache. Clinical studies have shown that female migraine patients typically experience a significant reduction in headache severity and frequency during late pregnancy; however, the underlying mechanisms remain unclear, and suitable animal models for investigating migraine during pregnancy are lacking. In this study, we established a pregnant chronic migraine rat model and found that oxytocin (OT) expression was markedly upregulated in the paraventricular nucleus (PVN) and nucleus of the solitary tract (NTS) during late pregnancy, and viral tracing confirmed the oxytocinergic axonal projections from the PVN to the NTS. Repeated intranasal OT administration and AAV9-mediated OT overexpression in either the PVN or NTS significantly reduced CGRP expression, neuronal activation, and pro-inflammatory cytokine levels (IL-1α, IL-1β, IL-6, TNF-α) in the NTS, and alleviated hyperalgesic behaviors. Further investigations demonstrated that OT mediated these protective effects by downregulating the extracellular matrix (ECM)-receptor interaction signaling pathway and integrin receptor expression. In summary, this study establishes a pregnant chronic migraine rat model and confirms that elevated endogenous OT during late pregnancy can alleviate neuroinflammation and hyperalgesic behaviors through regulation of the ECM-receptor interaction signaling pathway, providing new mechanistic insights into migraine relief during pregnancy and laying a foundation for oxytocin-based therapeutic strategies for migraine.