Dysfunctional astrocyte glutamate uptake in the hypothalamic paraventricular nucleus contributes to visceral pain and anxiety-like behavior in mice with chronic pancreatitis

Abstract

Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca²⁺ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca²⁺ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca²⁺ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2^PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2^PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.