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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.

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