Journal Article

Upregulation of NR2B Subunits of NMDA Receptors in the Lateral Parabrachial Nucleus Contributes to Chronic Pancreatitis Pain

Wu, Jing‐Lai, Kuang, Wen‐Qiong, Xu, Guang‐Yin, Yao, Jia‐He, Cao, Jing, Dou, Jing‐Heng, Zhang, Fu‐Chao, Zhu, Zheng‐Yan

2025

Overview

Aims Chronic pancreatitis (CP) is a localized or diffuse chronic progressive inflammation of the pancreas that can be caused by a variety of factors and is characterized by abdominal pain. However, the underlying mechanisms are poorly understood. Increasing evidence suggests that central sensitization plays a crucial role in the development of visceral pain, but the precise mechanisms of central neural processing remain unclear. Methods CP was induced using repeated intraperitoneal injections of caerulein in mice. Neurospecific anterograde tracing was achieved using herpes simplex virus type 1 (HSV‐1). Fiber photometry was used to assess neuronal activity. Optogenetic, chemogenetic, or pharmacological approaches were applied to manipulate the lateral parabrachial nucleus (LPB) glutamatergic neurons. The abdominal withdrawal threshold (AWT) was measured to evaluate the CP pain. A glutamate sensor was used to detect glutamate release in the LPB. Results In the present study, we demonstrated that glutamatergic neurons in the LPB are activated in CP mice, leading to the development of CP pain. Notably, glutamatergic release is increased in the LPB, and the increased release primarily mediates CP pain by binding to the N‐methyl‐D‐aspartate (NMDA) receptor rather than α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors. Specifically, this process involves the binding of the N‐Methyl‐D‐Aspartate Receptor Subunit 2B (NR2B) in the LPB, leading to the development of CP pain. Conclusions This study identified the NR2B subunits of NMDA receptors in the LPB as playing a critical role in the regulation of CP pain. A structural connection between the pancreas and the brain was established and identified the mechanisms through which the lateral parabrachial nucleus (LPB) modulates chronic pancreatitis pain.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Abdomen / Animals / Antibodies / Behavior / Brain research / Ceruletide - toxicity / Chronic pain / chronic pancreatitis pain / Fiber optics / glutamatergic neurons / Glutamatergic transmission / Glutamic Acid - metabolism / Glutamic acid receptors (ionotropic) / Herpes simplex / Information processing / lateral parabrachial nucleus / Male / Mice / Mice, Inbred C57BL / N-Methyl-D-aspartic acid receptors / Nervous system / Neurons - metabolism / Neurosciences / NR2B receptors / Original / Pain / Pancreas / Pancreatitis / Pancreatitis, Chronic - chemically induced / Pancreatitis, Chronic - complications / Pancreatitis, Chronic - metabolism / Parabrachial nucleus / Parabrachial Nucleus - metabolism / Photometry / Receptors, N-Methyl-D-Aspartate - biosynthesis / Receptors, N-Methyl-D-Aspartate - metabolism / Spinal cord / Up-Regulation - physiology / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid