Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes.
Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes.
复制标题
糖尿病大鼠初级感觉神经元的结肠过敏和电压门控钠通道的敏化。
DOI：
10.5056/jnm15091
复制
发表时间：
2016-01-31
影响因子：
3.4
通讯作者：
Xu GY
中科院分区：
文献类型：
--
作者：
Hu J;Song ZY;Zhang HH;Qin X;Hu S;Jiang X;Xu GY
长期糖尿病患者经常表现出肠道功能障碍和腹痛。然而，糖尿病患者腹痛的病理生理学仍然难以捉摸。本研究旨在探讨背根神经节（DRG）电压门控钠通道在糖尿病大鼠结肠高敏感性中的作用。糖尿病模型通过在成年雌性大鼠中单次腹腔注射链脲佐菌素（STZ; 65 mg/kg）诱导，而对照大鼠仅接受柠檬酸盐缓冲液。对结肠扩张的行为反应被用来确定大鼠结肠的敏感性。用DiI标记的DRG结肠投射神经元被急性分离，用于全细胞膜片钳记录测量兴奋性和钠通道电流。Western blot法检测结肠背根神经节NaV1.7和NaV1.8的表达。STZ注射产生了显着降低扩张阈值比对照组大鼠在回应结直肠扩张。STZ注射还使静息膜电位去极化，动作电位阈值超极化，基强度降低，2倍和3倍基强度和斜坡电流诱发的动作电位频率增加。此外，STZ注射增强神经元钠电流密度的DRG神经元支配结肠。与年龄和性别匹配的对照大鼠相比，STZ注射还导致结肠DRG中NaV1.7和NaV1.8表达的显著上调。我们的研究结果表明，STZ注射后神经元兴奋性增强，这可能是通过上调背根神经节中的NaV1.7和NaV1.8表达介导的，可能在糖尿病大鼠结肠超敏反应中起重要作用。
Patients with long-standing diabetes often demonstrate intestinal dysfunction and abdominal pain. However, the pathophysiology of abdominal pain in diabetic patients remains elusive. The purpose of study was to determine roles of voltage-gated sodium channels in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. Diabetic models were induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in adult female rats, while the control rats received citrate buffer only. Behavioral responses to colorectal distention were used to determine colonic sensitivity in rats. Colon projection DRG neurons labeled with DiI were acutely dissociated for measuring excitability and sodium channel currents by whole-cell patch clamp recordings. Western blot analysis was employed to measure the expression of NaV1.7 and NaV1.8 of colon DRGs. STZ injection produced a significantly lower distention threshold than control rats in responding to colorectal distention. STZ injection also depolarized the resting membrane potentials, hyperpolarized action potential threshold, decreased rheobase and increased frequency of action potentials evoked by 2 and 3 times rheobase and ramp current stimulation. Furthermore, STZ injection enhanced neuronal sodium current densities of DRG neurons innervating the colon. STZ injection also led to a significant upregulation of NaV1.7 and NaV1.8 expression in colon DRGs compared with age and sex-matched control rats. Our results suggest that enhanced neuronal excitability following STZ injection, which may be mediated by upregulation of NaV1.7 and NaV1.8 expression in DRGs, may play an important role in colonic hypersensitivity in rats with diabetes.