Xu Guang-Yin, Winston John H, Shenoy Mohan, Yin Huaizhi, Pasricha Pankaj Jay
Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine, Univ. of Texas Medical Branch, Galveston, Texas 77555, USA.
Am J Physiol Gastrointest Liver Physiol. 2006 Sep;291(3):G424-31. doi: 10.1152/ajpgi.00560.2005. Epub 2006 Apr 27.
Chronic pancreatitis (CP) is a relatively common disorder, characterized by glandular insufficiency and chronic, often intractable, pain. The mechanism of pain in CP is poorly understood. We have previously developed a model of trinitrobenzene sulphonic acid (TNBS)-induced CP that results in nociceptive sensitization in rats. This study was designed to examine changes in the excitability and alteration of voltage-gated K(+) currents of dorsal root ganglia (DRG) neurons innervating the pancreas. CP was induced in adult rats by an intraductal injection of TNBS. DRG neurons innervating the pancreas were identified by 1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate fluorescence labeling. Perforated patch-clamp recordings were made from acutely dissociated DRG neurons from control and TNBS-treated rats. Pancreas-specific DRG neurons displayed more depolarized resting potentials in TNBS-treated rats than those in controls (P < 0.02). Some neurons from the TNBS-treated group exhibited spontaneous firings. TNBS-induced CP also resulted in a dramatic reduction in rheobase (P < 0.05) and a significant increase in the number of action potentials evoked at twice rheobase (P < 0.05). Under voltage-clamp conditions, neurons from both groups exhibited transient A-type (I(A)) and sustained outward rectifier K(+) currents (I(K)). Compared with controls, the average I(A) but not the average I(K) density was significantly reduced in the TNBS-treated group (P < 0.05). The steady-state inactivation curve for I(A) was displaced by approximately 20 mV to more hyperpolarized levels after the TNBS treatment. These data suggest that TNBS treatment increases the excitability of pancreas-specific DRG neurons by suppressing I(A) density, thus identifying for the first time a specific molecular mechanism underlying chronic visceral pain and sensitization in CP.
慢性胰腺炎（CP）是一种相对常见的疾病，其特征为腺功能不全以及慢性、常难以治愈的疼痛。CP疼痛的机制尚不清楚。我们之前建立了一种三硝基苯磺酸（TNBS）诱导的CP模型，该模型会导致大鼠伤害性感受敏化。本研究旨在检查支配胰腺的背根神经节（DRG）神经元的兴奋性变化以及电压门控钾（K(+)）电流的改变。通过导管内注射TNBS在成年大鼠中诱导CP。通过1,1'-二油酰基-3,3,3',3-四甲基吲哚羰花青甲磺酸盐荧光标记来识别支配胰腺的DRG神经元。从对照大鼠和TNBS处理大鼠急性分离的DRG神经元进行穿孔膜片钳记录。胰腺特异性DRG神经元在TNBS处理的大鼠中比在对照大鼠中表现出更去极化的静息电位（P < 0.02）。TNBS处理组的一些神经元表现出自发放电。TNBS诱导的CP还导致阈强度（P < 0.05）显著降低，以及在两倍阈强度时诱发的动作电位数量显著增加（P < 0.05）。在电压钳条件下，两组神经元均表现出瞬时A型（I(A)）和持续外向整流钾（K(+)）电流（I(K)）。与对照组相比，TNBS处理组中I(A)的平均密度显著降低，但I(K)的平均密度未降低（P < 0.05）。TNBS处理后，I(A)的稳态失活曲线向更超极化水平位移约20 mV。这些数据表明，TNBS处理通过抑制I(A)密度增加了胰腺特异性DRG神经元的兴奋性，从而首次确定了CP中慢性内脏疼痛和敏化的特定分子机制。
