Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats

Yang Bai,Ying-Qi Li,Dan Ren,Hong-Ke Sun,Xi-Nan Yi,Yan-Bing Chen,Ming-Ming Zhang,Ting Zhang,Xin-Tong Qiu,Hui Li,Ying-Biao Chen,Bo-Yuan Fan,Yun-Qing Li,Tao Chen,Li-Tian Ma

doi:10.1186/s13041-019-0497-5

Abstract

Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. This study was designed to examine the role of anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). Abdomen hyperalgesia and anxiety were assessed by von Frey filament and open field tests, respectively. Two weeks after surgery, the activation of aIC was indicated by FOS immunohistochemical staining and electrophysiological recordings. Expressions of VGluT1, NMDAR subunit NR2B and AMPAR subunit GluR1 were analyzed by immunoblottings. The regulatory roles of aIC in hyperalgesia and pain-related anxiety were detected via pharmacological approach and chemogenetics in CP rats. Our results showed that TNBS treatment resulted in long-term hyperalgesia and anxiety-like behavior in rats. CP rats exhibited increased FOS expression and potentiated excitatory synaptic transmission within aIC. CP rats also showed up-regulated expression of VGluT1, and increased membrane trafficking and phosphorylation of NR2B and GluR1 within aIC. Blocking excitatory synaptic transmission significantly attenuated abdomen mechanical hyperalgesia. Specifically inhibiting the excitability of insular pyramidal cells reduced both abdomen hyperalgesia and pain-related anxiety. In conclusion, our findings emphasize a key role for aIC in hyperalgesia and anxiety of painful CP, providing a novel insight into cortical modulation of painful CP and shedding light on aIC as a potential target for neuromodulation interventions in the treatment of CP.

Highlights

Sustained abdominal pain is the most prominent feature of chronic pancreatitis (CP)
trinitrobenzene sulfonic acid (TNBS)-induced abdomen hypersensitivity and anxiety The validity of CP model was evidenced by histopathological changes of pancreatic tissue, such as acinar atrophy, inflammatory infiltration and stromal fibrosis (Fig. 1a-c)
Owing to the damage of acinar cells, TNBS-treated rats exhibited increased contents of serum amylase and lipase on post-operation day (POD) 3, which decreased along the course of CP and returned to baseline on POD 28 (Fig. 1d, e)

Summary

Introduction

Sustained abdominal pain is the most prominent feature of chronic pancreatitis (CP). It takes a heavy toll on the well-being of CP patients and renders a tough challenge for both gastroenterologists and pain physicians [1]. Long-term potentiation (LTP) of insular excitatory synaptic transmission is believed to mediate pathological pain [12, 13]. Excitatory synaptic transmission within IC was enhanced during neuropathic pain, which was attributable to enhanced presynaptic release of glutamate and postsynaptic recruitment of AMPAR and NMDAR [14, 15]. Both insular lesion [16, 17] and drugs aiming at inhibiting insular glutamatergic transmission [14, 15, 18, 19] or plastic changes [20] exerted analgesic effects in neuropathic and inflammatory pain models. Whether there exist such neuroplastic changes within IC under the condition of painful CP receives few attentions

Methods

Results

Conclusion