Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, Fourth Military Medical University, No. 169, West Chang-le Road, Xi'an, 710032, China.
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Mol Brain. 2019 Sep 4;12(1):76. doi: 10.1186/s13041-019-0497-5.
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.
中央敏化在慢性胰腺炎 (CP) 引起的慢性疼痛维持中起着关键作用，但皮质对疼痛 CP 的调节仍然难以捉摸。本研究旨在研究前岛叶皮层 (aIC) 在 CP 大鼠模型中痛觉过敏发病机制中的作用。CP 通过管腔内给予三硝基苯磺酸 (TNBS) 诱导。通过 von Frey 纤维和旷场试验分别评估腹部痛觉过敏和焦虑。手术后 2 周，通过 FOS 免疫组织化学染色和电生理记录指示 aIC 的激活。通过免疫印迹分析 VGluT1、NMDAR 亚基 NR2B 和 AMPAR 亚基 GluR1 的表达。通过药理学方法和 CP 大鼠中的化学遗传学检测 aIC 在痛觉过敏和与疼痛相关的焦虑中的调节作用。我们的结果表明，TNBS 处理导致大鼠长期痛觉过敏和焦虑样行为。CP 大鼠表现出 aIC 内 FOS 表达增加和兴奋性突触传递增强。CP 大鼠还表现出 aIC 内 VGluT1 表达上调，以及 NR2B 和 GluR1 的膜转运和磷酸化增加。阻断兴奋性突触传递可显著减轻腹部机械性痛觉过敏。具体地，抑制岛叶锥体神经元的兴奋性可降低腹部痛觉过敏和与疼痛相关的焦虑。总之，我们的研究结果强调了 aIC 在疼痛 CP 的痛觉过敏和焦虑中的关键作用，为皮质对疼痛 CP 的调节提供了新的见解，并表明 aIC 作为 CP 治疗中神经调节干预的潜在靶点。
