Nucleus tractus solitarius mediates hyperalgesia induced by chronic pancreatitis in rats

被引:21
作者
Bai, Yang [1 ,2 ]
Chen, Ying-Biao [3 ]
Qiu, Xin-Tong [1 ,2 ]
Chen, Yan-Bing [1 ,2 ]
Ma, Li-Tian [1 ,2 ]
Li, Ying-Qi [4 ]
Sun, Hong-Ke [4 ]
Zhang, Ming-Ming [1 ,2 ]
Zhang, Ting [1 ,2 ]
Chen, Tao [1 ,2 ]
Fan, Bo-Yuan [4 ]
Li, Hui [1 ,2 ]
Li, Yun-Qing [1 ,2 ,5 ]
机构
[1] Fourth Mil Med Univ, Dept Anat Histol & Embryol, 169 West Changle Rd, Xian 710032, Shaanxi, Peoples R China
[2] Fourth Mil Med Univ, KK Leung Brain Res Ctr, 169 West Changle Rd, Xian 710032, Shaanxi, Peoples R China
[3] Fujian Hlth Coll, Dept Anat, Fuzhou 350101, Fujian, Peoples R China
[4] Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Cardiol, Xian 710004, Shaanxi, Peoples R China
[5] Hainan Med Univ, Joint Lab Neurosci Hainan Med Univ & Fourth Mil M, Haikou 571199, Hainan, Peoples R China
基金
中国国家自然科学基金;
关键词
Rat; Chronic pancreatitis; Visceral hypersensitivity; Nucleus tractus solitarius; Excitatory synaptic transmission; VESICULAR GLUTAMATE TRANSPORTERS; NOXIOUS VISCERAL STIMULUS; BRAIN-STEM PROJECTIONS; NEUROPATHIC PAIN; VAGUS NERVE; SYNAPTIC-TRANSMISSION; RECEPTOR SUBUNIT; MOTOR COMPONENTS; SPINAL-CORD; NEURONS;
D O I
10.3748/wjg.v25.i40.6077
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP. AIM To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis. METHODS CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats. RESULTS TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 +/- 1.12 Hz in CP rats vs 2.55 +/- 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 +/- 1.39 pA in CP rats vs 14.71 +/- 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 +/- 1.02 g in CNQX group, 8.00 +/- 0.81 g in AP-5 group and 1.10 +/- 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 +/- 2.55 g in Gi group, 2.00 +/- 1.37 g in Gq group, and 2.36 +/- 0.67 g in mCherry group, P < 0.01). CONCLUSION Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.
引用
收藏
页码:6077 / 6093
页数:17
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