Early-life stress (ELS) is a high-risk factor for the development of chronic visceral pain in adulthood. Emerging evidence suggests that mast cells play a key role in the development of visceral hypersensitivity through interaction with neurons. The sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of visceral pain. However, the precise mechanism by which mast cells and CRF neurons interact in the PVN in the pathogenesis of visceral hypersensitivity remains elusive. In the present study, we used neonatal maternal separation (MS), an ELS model, and observed that neonatal MS induced visceral hypersensitivity and triggered PVN mast cell activation in adult rats, which was repressed by intra-PVN infusion of the mast cell stabilizer disodium cromoglycate (cromolyn). Wild-type (WT) mice but not mast cell-deficient KitW-sh/W-sh mice that had experienced neonatal MS exhibited chronic visceral hypersensitivity. MS was associated with an increase in the expression of proinflammatory mediators, the number of CRF+ cells and CRF protein in the PVN, which was prevented by intra-PVN infusion of cromolyn. Furthermore, we demonstrated that intra-PVN infusion of the mast degranulator compound 48/80 significantly induced mast cell activation, resulting in proinflammatory mediator release, CRF neuronal sensitization, and visceral hypersensitivity, which was suppressed by cromolyn. Overall, our findings demonstrated that neonatal MS induces the activation of PVN mast cells, which secrete numerous proinflammatory mediators that may participate in neighboring CRF neuronal activity, ultimately directly inducing visceral hypersensitivity in adulthood.
Keywords: Corticotropin-releasing factor (CRF); Mast cells; Neonatal maternal separation; Paraventricular nucleus; Visceral hypersensitivity.
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