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

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.

NR2B receptors; chronic pancreatitis pain; glutamatergic neurons; lateral parabrachial nucleus.