Spinal Cord-Mediated Acute Neurogenic Inflammation

脊髓介导的急性神经源性炎症

• 批准号: 8022613
• 负责人: Qing Lin
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022613
• 关键词: Abbreviations; Acute; Adenosine; Adenosine Triphosphate; Adrenergic Agents; Adrenergic Receptor; Affect; Afferent Neurons; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Blood flow; C Fiber; Calcitonin Gene-Related Peptide; Capsaicin; Chronic Bronchitis; Cutaneous; Data; Distal; Dorsal; Dose; Edema; Electrons; Esthesia; Excision; Fiber; Figs - dietary; GABA Receptor; Glutamate Receptor; Goals; Grant; Immunofluorescence Immunologic; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injection of therapeutic agent; Injury; Interneurons; Interstitial Cystitis; Intra-Arterial Injections; Lead; Light; Measurement; Mechanics; Mediating; Microscopic; Migraine; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve; Neurogenic Inflammation; Neurons; Neuropeptides; Neurotransmitters; Nociception; Nociceptors; Norepinephrine; Pain; Pathogenesis; Peripheral; Phosphorylation; Play; Principal Investigator; Process; Progress Reports; Protein Kinase C; Proteins; Purinoceptor; Rattus; Receptor Activation; Reflex action; Research Personnel; Rhizotomy procedure; Role; Sensory; Signal Transduction; Signal Transduction Pathway; Skin; Spinal; Spinal Cord; Spinal Ganglia; Staining method; Stains; Stimulus; Substance P; Sympathectomy; Testing; Thick; Tissues; Up-Regulation; Vanilloid; Vasodilation; Western Blotting; adrenergic; afferent nerve; base; citrate carrier; clinically relevant; dorsal horn; inflammatory pain; intradermal injection; neurotransmitter release; novel; programs; receptor; receptor expression; receptors for activated C kinase; response; spinal nerve posterior root; tripolyphosphate; vanilloid receptor subtype 1

DESCRIPTION (provided by applicant): Neurogenic inflammation contributes to many clinically relevant states, including arthritis, inflammatory bowel disease, chronic bronchitis, migraine and interstitial cystitis. Such a type of inflammation has been known to be initiated by release of inflammatory substances from sensory nerve terminals by which painful sensation may be caused and even exacerbated. In order to investigate its mechanisms, we have experimentally established an acute model of neurogenic inflammation by using an intradermal capsaicin (CAP) injection. The long-term goal of the proposed studies is to elucidate how neurogenic inflammation is initiated by activation of transient receptor potential vanilloid-1 (TRPVO receptors, then maintained by triggering the centrally mediated antidromic activity, dorsal root reflexes (DRRs) to exacerbate inflammatory pain, and how sympathetic-sensory interactions modulate the neurogenic inflammation. Uncovering these mechanisms will lead to improvements in anti-inflammatory therapies. The overall hypothesis of the present proposal is that activation of TRPV-i receptors either by intradermal injection of CAP or tissue injury initiates neurogenic inflammation that will then be maintained and develops by triggering DRRs. Sympathetic-sensory interactions modulate the neurogenic inflammation by regulating the functional activity of TRPVi receptors via activating signal transduction cascades, such as protein kinase C (PKC). Specific Aim 1 is to determine if neurogenic inflammation following CAP injection involves triggering DRRs that cause the release of calcitonin gene-related peptide and/or substance P from primary afferent nociceptors and if this process would in turn enhance the CAP-induced sensitization of primary afferent nociceptors, as well as analyze if this process is initiated by activation of TRPN/! receptors. Specific Aim 2 is to examine if activation of the PX/! receptors in primary afferent nociceptors plays an important role in enhancing DRRs by activating GABAergic interneurons in dorsal horn circuits. Specific Aim 3 is to determine if phosphorylation of PKC takes place in the primary afferent neurons when neurogenic inflammation is initiated and develops, and if TRPN/T receptors are up-regulated by the phosphorylation of PKC. Specific Aim 4 is to examine if sympathetic effects on neurogenic inflammation by release of norepinephrine and adenosine 5'-triphosphate are done by modulating the function of TRPNA, receptors via the PKC cascade. The experimental approaches that will be used include electrophysiological recordings and pharmacological modulation of proteins involved in nociceptive signal transduction, blood flow and paw-thickness measurements to reflect neurogenic inflammation induced by CAP injection, and immunohistochemical and Western blotting studies to analyze changes in the expression of phosphorylated receptors and PKC before and after CAP injection.

描述（由申请人提供）：神经源性炎症有助于许多临床相关状态，包括关节炎，炎症性肠病，慢性支气管炎，偏头痛和间质性膀胱炎。已知这种炎症是通过从感觉神经末端释放炎症物质引发的，通过这种炎症物质可能会引起疼痛的感觉，甚至加剧。为了研究其机制，我们通过使用皮内辣椒素（CAP）注射来实验建立了神经源性炎症的急性模型。提出的研究的长期目标是阐明如何通过激活瞬态受体潜在的香草素1（TRPVO受体（然后通过触发中心介导的抗中心抗体活性）维持的神经发生炎症，并保持背面反射（DRR），以使这些炎症的炎症性疼痛和炎症的疾病疾病的疾病变化如何，使它们的相互促进性疾病的疾病变化。导致抗炎疗法的改善。当前建议的总体假设是，通过对CAP内注射或组织损伤的激活或组织损伤会启动神经发生的炎症，然后通过触发drr触发的动态传播来维持并发展。 cascades, such as protein kinase C (PKC). Specific Aim 1 is to determine if neurogenic inflammation following CAP injection involves triggering DRRs that cause the release of calcitonin gene-related peptide and/or substance P from primary afferent nociceptors and if this process would in turn enhance the CAP-induced sensitization of primary afferent nociceptors, as well as analyze if this process is initiated by激活TRPN/！ PKC的磷酸化是通过释放去甲肾上腺素和腺苷5'-三磷酸来检查对神经发生的炎症的磷酸化的上调。在伤害性信号转导中，血流和爪子厚度测量值反映了由帽注射引起的神经源性炎症，以及免疫组织化学和蛋白质印迹研究，以分析磷酸化受体和PKC表达的变化。