DORSAL SPINAL CORD STIMULATION--VASODILATOR MECHANISMS

描述(改编自申请人的摘要)：电刺激 脊髓背部(SCS)用于缓解患者的疼痛 周围血管疾病(PVD)。临床和基础科学研究表明 SCS对PVD的有益作用与血液增加有关 流向四肢。申请人实验室之前的工作已经完成 证明SCS诱导的血管扩张是由逆行激活介导的 初级传入神经元导致血管扩张剂多肽从 周围感觉神经末梢。这项提案的总体目标是 探讨外周神经逆行调节机制的研究 血管对SCS的反应。为解决这一问题，提出了四个具体目标 假设。在具体目标1中，调查人员将检验以下假设 血管活性多肽的逆行释放是高血压的主要机制 SCS诱导的临床相关强度的血管扩张。该协议将 在麻醉的和清醒的、自由活动的动物身上进行检查。特定的 目的2将验证假设，SCS诱导的逆行激活 传入神经可通过测量增加的 感觉神经中的电活动。该协议包括评估 对SCS反应的传入神经活动。在具体目标3中，调查人员 将检验这样的假设，即SCS的逆行调节效应产生 血管通透性增加，而通透性增加是由于 感觉神经释放P物质激活神经激肽-1受体 末梢位于外周血管系统。该协议包括评估 伊文氏蓝检测外周血管通透性的变化 单星蓝从血管内向外的渗出和移位 血管外空间。调查人员还将审查 降钙素基因相关肽对SCS通透性变化的影响具体而言 目的4他们假设SCS的逆行效应需要激活 脊髓中的突触路径。该协议用于寻址外围设备 脊髓内微量注射三七总皂甙前后的血管扩张作用 γ-氨基丁酸和兴奋性氨基酸的药理拮抗剂 酸。全面调查的结果将进一步确定 SCS在周围血管机制和脊髓通路中的作用 参与引起这种效应的。结果也将证明 将SCS作为一种工具来调查 逆行诱导的血管活性物质从感觉神经末梢释放。 最终，从这些研究中获得的信息具有潜在的临床应用价值。 不仅适用于周围血管疾病，也适用于各种疾病 伤口愈合、组织炎症、心绞痛、 自主神经反射障碍和雷诺现象。

DESCRIPTION (Adapted from the applicant's abstract): Electrical stimulation of the dorsal spinal cord (SCS) is used to provide pain relief in patients with peripheral vascular disease (PVD). Clinical and basic science studies indicate that the beneficial effect of SCS in PVD is associated with increased blood flow to the extremities. Previous work from the applicant's laboratory has demonstrated that SCS-induced vasodilation is mediated by antidromic activation of primary afferent neurons resulting in release of a vasodilator peptide from peripheral sensory nerve endings. The overall goal of this proposal is to investigate the antidromic mediated mechanisms involved in the peripheral vascular responses to SCS. Four Specific Aims are proposed to address this hypothesis. In Specific Aim 1 the investigators will test the hypothesis that antidromic release of vasoactive peptides is the primary mechanism of SCS-induced vasodilation at clinically relevant intensities. This protocol will be examined in anesthetized and in conscious, freely moving animals. Specific Aim 2 will test the hypothesis that SCS-induced antidromic activation of afferent nerves can be directly demonstrated through measurement of increased electrical activity in sensory nerves. This protocol involves assessment of afferent nerve activity in response to SCS. In Specific Aim 3 the investigators will test the hypothesis that the antidromic mediated effects of SCS produce increased vascular permeability, and the increased permeability is due to activation of neurokinin-1 receptors by Substance P release from sensory nerve endings in the peripheral vasculature. This protocol involves assessment of changes in peripheral vascular permeability through examination of Evan's blue extravasation and translocation of Monastral blue from intravascular to extravascular spaces. The investigators also will examine the contribution of calcitonin gene-related peptide on permeability changes due to SCS. In Specific Aim 4 they hypothesize that the antidromic effects of SCS require activation of synaptic pathways in the spinal cord. This protocol addresses the peripheral vasodilator effects of SCS before and after intraspinal microinjection of pharmacological antagonists of gamma-aminobutyric acid and excitatory amino acids. Results of the overall investigation will further define the antidromic effects of SCS related to peripheral vascular mechanisms and spinal pathways involved in eliciting this effect. The results also will demonstrate the importance of using SCS as a tool to investigate the effects of antidromic-induced release of vasoactive substances from sensory nerve endings. Ultimately, information obtained from these studies has potential clinical application not only to peripheral vascular disease but also to diverse processes such as wound healing, tissue inflammation, angina pectoris, autonomic dysreflexia and Raynaud's phenomenon.