Paraventricular Mast Cell-Derived Histamine Activates CRH Neurons to Mediate Adult Visceral Hypersensitivity Induced by Neonatal Maternal Separation

Author:

Chen Ziyang1,Zhou Tiantian2,Li Yunfan1,Li Tingting3,Ding Zhengnian1,Liu Li3

Affiliation:

1. Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

2. Department of Anesthesiology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliate with Nanjing University of Chinese Medicine, Nanjing 210014, China

3. Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

Abstract

Neonatal maternal separation (NMS) is an early-life stress (ELS) that can result in adult visceral hypersensitivity, which is usually manifested as chronic visceral pain. Although mast cells and corticotropin-releasing hormone (CRH) neurons are involved in stress response, whether there is an interaction between mast cells and CRH neurons in hypothalamic paraventricular nucleus (PVN) during the ELS-induced visceral hypersensitivity remains elusive. Herein, we established an NMS model by separating neonatal mice from their mothers, and observed that these mice presented visceral hypersensitivity in adulthood, as indicated by elevated abdominal withdrawal reflex and lowered visceral pain threshold. The NMS-induced adult visceral hypersensitivity was accompanied by activation of mast cells and CRH neurons in PVN. Also, NMS increased the histamine content (an inflammatory mediator mainly released by mast cells) and histamine H2 receptor (H2R) expression of CRH neurons in PVN. Remarkably, intra-PVN administration with mast cell stabilizer attenuated the NMS-induced CRH neuronal activation and adult visceral pain, while histamine administration showed the opposite effects. Moreover, intra-PVN injection with H2R antagonist alleviated the NMS-induced CRH neuronal activation, PKA and CREB phosphorylation, and importantly, adult visceral pain. Together, our findings revealed a role of an interaction between paraventricular mast cells and CRH neurons in NMS-induced adult visceral hypersensitivity, thereby providing a perspective for the management of visceral pain.

Funder

Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University

Publisher

MDPI AG

Subject

General Neuroscience

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