Xu Guang-Yin, Winston John H, Shenoy Mohan, Yin Huaizhi, Pendyala Swaroop, Pasricha Pankaj Jay
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Gastroenterology. 2007 Oct;133(4):1282-92. doi: 10.1053/j.gastro.2007.06.015. Epub 2007 Jun 20.
BACKGROUND & AIMS: The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP.
CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat's nocifensive behavior to electrical stimulation of the pancreas.
CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals.
TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation.
慢性胰腺炎（CP）中胰腺痛觉过敏的神经生物学基础尚不清楚，需要确定新的治疗靶点。我们的目的是研究瞬时受体电位香草酸亚型1（TRPV1），一种伤害性刺激的关键整合蛋白，在CP大鼠模型胰腺疼痛发病机制中的作用。
通过向大鼠胰管内注射三硝基苯磺酸诱导CP。采用穿孔膜片钳技术测量胰腺特异性背根神经节（DRG）神经元中的TRPV1电流。激光捕获显微切割后，用逆转录聚合酶链反应测量这些神经元中TRPV1的mRNA表达。还使用TRPV1特异性抗体进行了免疫荧光和蛋白质印迹分析。通过大鼠对胰腺电刺激的伤害性防御行为评估胰腺痛觉过敏。
CP与辣椒素诱导的电流密度增加4倍相关（P <.02），同时对辣椒素产生反应的胰腺特异性DRG神经元比例增加（对照组为52.9%，CP组为79.0%；P <.05）。CP还与整个胸段DRG和胰腺特异性感觉神经元中TRPV1在信使RNA和蛋白质水平的表达显著增加相关。对CP大鼠全身给予TRPV1拮抗剂SB - 366791可显著降低内脏疼痛行为和牵涉性躯体痛觉过敏，但对对照动物无效。
TRPV1上调和敏化是导致CP痛觉过敏的一种特定分子机制，是治疗炎症引起的胰腺痛觉过敏的一个有效靶点。
