Bolyard Lori A, Van Looy James W, Vasko Michael R
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA Program in Medical Neurobiology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
Pain. 2000 Dec 1;88(3):277-285. doi: 10.1016/S0304-3959(00)00341-9.
Sensitization of sensory neurons is a critical component of hypersensitivity that occurs during chronic pain and inflammation. Questions remain, however, whether this sensitization depends on the continuous activation of signal transduction pathways in sensory neurons, whether the sensitization persists once the agent causing sensitization is removed, and whether downregulation occurs in the ability of these neurons to be sensitized. Because activation of the cAMP transduction cascade produces acute sensitization in rat sensory neurons, we examined whether continuous activation of the cAMP pathway augments bradykinin-stimulated release of immunoreactive substance P and immunoreactive calcitonin gene-related peptide from embryonic rat sensory neurons grown in culture. A 20 min exposure to 1 microM forskolin enhances bradykinin-stimulated release of both peptides. This ability of forskolin to sensitize sensory neurons persists even when the neurons are exposed to forskolin for 24 h or 7 days suggesting that there is no downregulation of the response. One hour after the removal of forskolin, however, the bradykinin-evoked release returned to control values. In a similar manner, the content of immunoreactive cAMP in the cultures is elevated in cells exposed to forskolin for 20 min, even after 24 h or 7 days of forskolin treatment, but returns to control levels after forskolin removal. When sensory neurons are treated with an inflammatory cocktail for 20 min, potassium-stimulated peptide release is significantly elevated, independent of whether the cells were pre-exposed to inflammatory mediators for 24 h. Potassium-stimulated release was not elevated 1 h after removal of the inflammatory cocktail. These data suggest that rat sensory neurons are capable of undergoing a long-term sensitization that does not downregulate, but requires the continual presence of a sensitizing agent.
感觉神经元的敏化是慢性疼痛和炎症期间发生的超敏反应的关键组成部分。然而，尚存在一些问题，即这种敏化是否依赖于感觉神经元中信号转导通路的持续激活，在引起敏化的因素去除后敏化是否持续存在，以及这些神经元的敏化能力是否会发生下调。由于cAMP转导级联的激活在大鼠感觉神经元中产生急性敏化，我们研究了cAMP途径的持续激活是否会增强缓激肽刺激培养的胚胎大鼠感觉神经元释放免疫反应性P物质和免疫反应性降钙素基因相关肽。暴露于1μM毛喉素20分钟可增强缓激肽刺激的这两种肽的释放。即使神经元暴露于毛喉素24小时或7天，毛喉素使感觉神经元敏化的这种能力仍然存在，这表明反应没有下调。然而，在去除毛喉素1小时后，缓激肽诱发的释放恢复到对照值。以类似的方式，在暴露于毛喉素20分钟的细胞中，培养物中免疫反应性cAMP的含量升高，即使在毛喉素处理24小时或7天后也是如此，但在去除毛喉素后恢复到对照水平。当感觉神经元用炎症混合物处理20分钟时，钾刺激的肽释放显著升高，与细胞是否预先暴露于炎症介质24小时无关。在去除炎症混合物1小时后，钾刺激的释放没有升高。这些数据表明，大鼠感觉神经元能够经历长期敏化，这种敏化不会下调，但需要敏化剂的持续存在。
