PAIN, SUPRASPINAL SEROTONIN AND NEUROTROPHIC FACTORS

纤维肌痛是痛觉过敏或痛觉异常综合征的一个子集，其特征是伤害性加工和神经内分泌功能失调。观察到慢性全身性疼痛以及内分泌和自主神经对应激的反应降低。显然，脊髓上系统调节伤害性通路，但我们对参与慢性疼痛通路的神经调节剂的了解仍然不完整。在治疗方面，改变5-羟色胺能神经传递的药物在这些疾病中显示出适度的效果。本研究将在一个慢性疼痛的动物模型中，利用体内微透析来研究在内分泌(下丘脑室旁核)和疼痛调节系统(丘脑腹侧核)中重要的棘上部位的单胺释放。此外，还将评估慢性疼痛对自主神经系统反应性的影响。神经营养因子NGF、成纤维细胞生长因子-1和成纤维细胞生长因子-2在中枢神经系统中有显著的表达，然而，关于它们在慢性疼痛中的表达如何变化的信息很少。这些生长因子的原位杂交和免疫组织化学定位将在佐剂性关节炎大鼠(慢性疼痛模型)、部分坐骨神经结扎大鼠(急性疼痛模型)和假手术对照组大鼠的脑内进行。体内实验将利用抗原寡核苷酸技术来调节c-fos、NGF、成纤维细胞生长因子-1和成纤维细胞生长因子-2的表达。微透析将使我们能够动态评估抗原寡核苷酸注射后大鼠大脑特定区域的5-羟色胺、P物质和神经生长因子的水平。这一提议将提供一种新的方法来动态测量参与伤害性信息传递的关键化合物。

Fibromyalgia comprises a subset of hyperalgesic or allodynic syndromes characterized by a dysregulation of nociceptive processing and neuroendocrine function. Chronic generalized pain together with decreased endocrine and autonomic responsiveness to stress has been observed. Clearly, supraspinal systems regulate nociceptive pathways, but our understanding of the neuromodulators participating in chronic pain pathways is quit incomplete. Therapeutically, drugs that alter serotonergic neurotransmission show modest effectiveness in these disorders. This study will utilize in vivo microdialysis to investigate monoamine release in supraspinal sites important in endocrine (paraventricular nucleus of the hypothalamus) and pain regulating (ventral lateral thalamus) systems in an animal model of chronic pain. In addition, the effects of chronic pain on responsiveness of the autonomic nervous system will also be assessed. Neurotrophic factors NGF, FGF-1 and FGF-2 are prominently expressed in the central nervous system however, there is a paucity of information on how their expression changes in the setting of chronic pain. In situ hybridization and immunohistochemical localization of these growth factors will be conducted on brain from Sprague-Dawley rats with adjuvant induced arthritis (a model of chronic pain), rats having undergone partial sciatic nerve ligation (a model of acute pain) and sham treated control rats. In vivo experiments will utilize antigens oligonucleotide technology to modulate c-fos, NGF, FGF-1 and FGF-2 expression. Microdialysis will allow us to dynamically assess Serotonin, Substance P and NGF levels in selected regions of rat brain following antigens oligonucleotide delivery. This proposal will provide a novel approach to dynamically measure critical compounds involved in nociceptive transmission.