Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis
Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis
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DOI：
10.1016/j.ebiom.2019.07.055
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发表时间：
2019-08-01
期刊：
影响因子：
11.1
通讯作者：
Ceyhan, Guralp O.
中科院分区：
文献类型：
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作者：
Demir, Ihsan Ekin;Heinrich, Tobias;Ceyhan, Guralp O.
背景：众所周知，胰腺癌/PCa或慢性胰腺炎/CP引起的疼痛对最强的止痛药有抵抗力。在这里，我们的目的是在破译特定的分子介质的疼痛在胰腺癌阶段的胰腺疾病，并发现新的translational targets.Methods：我们进行了系统的，定量分析的神经递质/neuroenzmye档案内胰腺内的神经CP和PCa患者。离体神经元培养治疗与人类胰腺提取物，条件基因工程敲除小鼠模型的PCa和CP，和蛙皮素诱导的CP模型被用来探索治疗潜力的确定targets.Findings：我们确定了一个独特的富集神经元一氧化氮合酶（nNOS）在胰腺神经CP患者的疼痛严重程度增加。用CP患者的胰腺组织提取物处理的离体神经元培养物和脑源性神经营养因子缺陷（BDNF+/-）小鼠的就业揭示了nNOS的神经元富集是在逐渐破坏的胰腺组织中的BDNF损失的结果。从机制上讲，nNOS上调的感觉神经元诱导类胰蛋白酶分泌的神经周肥大细胞。在几种遗传诱导的无痛PCa小鼠模型（KPC，KC小鼠）或CP（Ptf 1a-Cre; Arg 5（f1/f1））与高分泌/蛙皮素诱导的疼痛CP小鼠模型的头对头比较中，我们发现，在疼痛的蛙皮素-CP模型中存在类似的nNOS富集，但在无痛遗传模型中不存在。因此，小鼠患有疼痛的雨蛙素诱导的CP可以显着缓解治疗后，与特定的nNOS抑制剂NPLA.Interpretation：我们提出nNOS抑制作为一种新的策略来治疗CP难以忍受的疼痛。(C)2019年，任作家。由爱思唯尔公司出版
Background: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets.Methods: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets.Findings: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNI loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Arg5(f1/f1)) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA.Interpretation: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. (C) 2019 The Authors. Published by Elsevier B.V.