NEURONAL NITRIC OXIDE SYNTHASE IN NEUROPATHIC PAIN

这项建议的长期目标是了解周围神经损伤（神经性疼痛）引起疼痛综合征的分子机制。 这些疼痛状态代表了影响牙齿和口面疾病患者日常生活质量的主要问题。 这些疾病通常对常规镇痛药无反应。 不幸的是，神经性疼痛的分子机制知之甚少，因此，没有特异性靶向的，有效的药理学药物可用于神经性疼痛治疗。 我们的初步数据表明，神经元型一氧化氮合酶（nNOS），一种催化一氧化氮（NO）的产生的酶的感觉神经元中的mRNA水平增加之间的相关性，和神经性疼痛（异常性疼痛）在大鼠模型的外周神经损伤的发展。 这表明，神经源性NO可能作为第二信使在加工和/或调制的神经病理性疼痛和nNOS的表达在转录或mRNA加工水平的调节可能强调神经可塑性周围神经损伤后。 本研究拟利用大鼠神经病理性疼痛模型，进一步研究nNOS表达在神经病理性疼痛发生中的作用机制。 将使用分子、免疫组织化学和药理学技术。 这项建议的具体目标是：1)通过比较未发生异常性疼痛的大鼠品系与易发生异常性疼痛的大鼠品系的nNOS mRNA和蛋白水平，研究神经性疼痛的发生与nNOS表达之间可能的遗传联系。 2)通过研究轴浆转运、反馈抑制和神经放电在nNOS调节和神经病理性疼痛发生中的作用，探讨nNOS调节的细胞机制及其与神经病理性疼痛发生的关系。 3)目的：观察神经病理性痛大鼠背根节（DRG）和脊髓中nNOS蛋白表达及其mRNA水平的变化。

The long term objective of this proposal is to understand the molecular mechanism of pain syndromes resulting from peripheral nerve injury (neuropathic pain). These pain states represent major problems affecting the quality of daily life of patients with dental and orofacial disorders. These disorders do not typically respond to conventional analgesics. Unfortunately, the molecular mechanisms of neuropathic pain are poorly understood and, as a consequence, there are no specifically targeted, effective pharmacological agents available for neuropathic pain treatment. Our preliminary data indicate a correlation between increased mRNA levels in sensory neurons of neuronal nitric oxide synthase (nNOS), an enzyme that catalyzes the production of nitric oxide (NO), and the development of neuropathic pain (allodynia) in a rat model of peripheral nerve injury. This suggests that neuronal-derived NO may serve as a second messenger in the processing and/or modulation of neuropathic pain and regulation of nNOS expression at the level of transcription or mRNA processing may underline the neuronal plasticity following peripheral nerve injury. This research proposal is designed to further study the mechanism and functional role of nNOS expression to the development of neuropathic pain using tissues of dorsal root ganglia (DRG) and spinal cord from a rat neuropathic pain model. Molecular, immunohistochemical and pharmacological techniques will be utilized. The specific aims of this proposal are:. 1) To examine a possible genetic linkage between development of neuropathic pain and expression of nNOS by comparing the nNOS mRNA and protein levels in a rat strain that does not develop allodynia with those in a rat strain susceptible to allodynia development. 2) To examine the cellular mechanism of nNOS regulation and its relation to the development of neuropathic pain by examining contributions of axoplasmic transport, feedback inhibition and nerve discharge on the regulation of nNOS and neuropathic pain development. 3) To correlate expression of nNOS protein with its mRNA levels at intervals during the development of allodynia and to examine the cellular localization of nNOS in DRG and spinal cord of rats with neuropathic pain.