Activation and recovery of the PGE2-mediated sensitization of the capsaicin response in rat sensory neurons
Activation and recovery of the PGE2-mediated sensitization of the capsaicin response in rat sensory neurons
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DOI：
10.1152/jn.1997.78.6.3154
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发表时间：
1997-12-01
影响因子：
2.5
通讯作者：
Nicol, GD
中科院分区：
文献类型：
--
作者：
Lopshire, JC;Nicol, GD
已知促炎性前列腺素可增强感觉神经元对各种刺激方式的敏感性，包括兴奋性化学剂辣椒素。在本报告中，我们检查了前列腺素 E-2 (PGE(2)) 增强辣椒素反应的能力，该反应是从胚胎大鼠分离并培养的感觉神经元记录的。先前的工作表明，环腺苷3',5'-单磷酸途径介导PGE(2)诱导的致敏的启动，然而，对于调节致敏恢复的途径知之甚少。因此，我们检查了控制敏化持续时间的神经元转导级联。 PGE(2) 治疗使辣椒素诱发的电流增强了两到三倍，然而，即使在前列腺素持续存在的情况下，这种敏化也是短暂的。 PGE 产生的致敏持续时间与细胞外 Ca2+ 浓度成反比，在暴露于 2 mM Ca2+-Ringer 的细胞中观察到恢复时间最短。记录移液管中加入Ca2+螯合剂双-(邻氨基苯氧基)-N,N,N',N'-四乙酸大大延长了敏化时间。在应用 PGE(2) 之前，使用一氧化氮合酶抑制剂硝基-L-精氨酸甲酯 (L-NAME) 或环鸟苷 3',5'-单磷酸 (GMP) 依赖性蛋白激酶抑制剂 KT-5823 进行预处理，即使在存在 2 mM Ca2+ 的情况下，也能延长致敏持续时间。相反，在含有 L-NAME 的 2 mM Ca2+-Ringer 中达到最大致敏后，添加一氧化氮供体（3-吗啉代亚胺或 s-亚硝基-n-乙酰青霉胺）或 8-Br-环状 GMP 会导致致敏水平迅速下降。在没有致敏作用的情况下，一氧化氮-环状 GMP 调节剂对辣椒素诱发的电流没有影响。因此，这些结果表明，辣椒素诱导的细胞内 Ca2+ 水平升高，通过一氧化氮途径导致环 GMP 产量增加，最终激活环 GMP 依赖性蛋白激酶。该蛋白激酶通过尚未确定的机制灭活或终止 PGE(2) 产生的致敏作用。
Pro-inflammatory prostaglandins are known to enhance the sensitivity of sensory neurons to various modalities of stimulation, including the excitatory chemical agent, capsaicin. In this report, we examined the capacity of prostaglandin E-2 (PGE(2)) to enhance the capsaicin response recorded from sensory neurons isolated from embryonic rats and grown in culture. Previous work demonstrated that the cyclic adenosine 3',5'-monophosphate pathway mediates initiation of the PGE(2)-induced sensitization, however, little is known about the pathways regulating the recovery from sensitization. Therefore, we examined the neuronal transduction cascades that control the duration of sensitization. Treatment with PGE(2) enhanced the capsaicin-evoked current by two-to threefold, however, this sensitization was transient even in the continued presence of prostaglandin. The duration of sensitization produced by PGE, was related inversely to the extracellular Ca2+ concentration with the shortest recovery times observed in cells exposed to 2 mM Ca2+-Ringer. Inclusion of the Ca2+ chelator, bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid, in the recording pipette greatly lengthened the period of sensitization. Pretreatment with either the nitric oxide synthase inhibitor, nitro-l-arginine methyl ester (L-NAME), or the inhibitor of the cyclic guanosine 3',5'-monophosphate (GMP)-dependent protein kinase, KT-5823, before the application of PGE(2) increased the duration of sensitization even in the presence of 2 mM Ca2+. In contrast, after attaining maximal sensitization in 2 mM Ca2+-Ringer containing L-NAME, the addition of either nitric oxide donors (3-morpholinosydnonimine or s-nitroso-n-acetylpenicillamine) or 8-Br-cyclic GMP led to a rapid decrease in the level of sensitization. In the absence of sensitization, nitric oxide-cyclic GMP modulating agents had no effect on the capsaicin-evoked current. Therefore, these results suggest that capsaicin-induced elevations in intracellular Ca2+ levels lead to an enhanced production of cyclic GMP, via the nitric oxide pathway, that ultimately activates cyclic GMP-dependent protein kinase. This protein kinase inactivates or terminates the sensitization produced by PGE(2) by an as yet unidentified mechanism.