NORADRENERGIC ANTINOCICEPTIVE MECHANISMS

去甲肾上腺素能镇痛机制

• 批准号: 2119478
• 负责人: SHARON L JONES
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-12-15 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2119478
• 关键词: afferent nerve; alpha adrenergic receptor; analgesics; antiadrenergic agents; cats; clonidine; dorsal horn; efferent nerve; electrostimulus; evoked potentials; immunocytochemistry; laboratory rat; locus coeruleus; neural inhibition; neural transmission; neuropharmacology; nontherapeutic iontophoresis; oncogenes; pons; sensory mechanism; stimulant /agonist

The long-term goals of this laboratory are to broaden our understanding of the organization and function of endogenous pain suppression systems that modulate spinal nociceptive transmission by using anatomical, pharmacological and physiological techniques. Elucidating the basic mechanisms of nociceptive processing will aid in the development of more effective and selective analgesic agents to treat pain. Aim 1 is designed to investigate the mechanisms and specificities of action of selective alpha adrenoceptor agonists on physiologically and anatomically characterize neurons in laminae I and II of the spinal cord dorsal horn. Aim 2 will investigate the contribution of endogenous descending noradrenergic systems to the modulation of laminae I and II dorsal horn neuronal activity produced by electrical stimulation in the nucleus raphe magnus and the nucleus locus coeruleus. Aim 3 will examine the density and distribution of noradrenergic varicosities on intracellularly labeled laminae I and II dorsal horn neurons. Superficial dorsal horn neurons receive input from nociceptive-specific primary afferents; thus, they particularly are relevant to spinal nociceptive processing. In Aim 4, the immunohistochemically localized c-fos oncogene will be utilized as a marker for non-specific neuronal activity, to determine which noradrenergic brainstem nuclei contribute to nucleus raphe magnus stimulation-produced inhibition of spinal nociceptive transmission. How descending inhibitory systems function as an integrated system within the brainstem to modulate spinal nociceptive processing is poorly understood; the proposed experiments will begin to explore this issue. The clinical potential of alpha adrenergic agonists as analgesic agents already has been recognized. Clonidine, an alpha2 adrenoceptor agonist, produces an analgesia when administered intrathecally to morphine-tolerant cancer patients. The importance of this finding to the treatment of chronic pain is readily apparent since few pharmacologic alternatives currently are available to treat pain in the opioid-tolerant patient. Achieving a better understanding of how exogenously applied alpha adrenoceptor agonists, and endogenous descending noradrenergic systems modulate spinal nociceptive transmission is of potential therapeutic importance to the development of more selective and effective analgesic agents.

该实验室的长期目标是扩大我们对 内源性疼痛抑制系统的组织和功能 通过使用解剖学来调节脊髓伤害性传递， 药理学和生理学技术。 阐明基本原理 伤害性处理机制将有助于开发更多 有效且选择性的镇痛剂来治疗疼痛。 目标 1 旨在研究行动的机制和特殊性 选择性α肾上腺素受体激动剂对生理学和 脊髓 I 和 II 层神经元的解剖学特征 背角。 目标 2 将调查内源性的贡献 降去甲肾上腺素能系统对 I 和 II 层的调节 电刺激产生的背角神经元活动 中缝大核和蓝斑核。 目标 3 将检查 去甲肾上腺素能静脉曲张的密度和分布 细胞内标记的层板 I 和 II 背角神经元。 浅 背角神经元接收来自伤害感受特异性初级神经元的输入 传入；因此，它们与脊髓伤害性感受特别相关 加工。 在目标 4 中，免疫组织化学定位的 c-fos 癌基因将是 用作非特异性神经元活动的标记，以确定哪些 去甲肾上腺素能脑干核对中缝大核有贡献 刺激产生的脊髓伤害性传递的抑制。 如何 下行抑制系统作为一个集成系统发挥作用 脑干调节脊髓伤害感受处理的机制尚不清楚； 拟议的实验将开始探讨这个问题。 α肾上腺素能激动剂作为镇痛剂的临床潜力 已经被认可了。 可乐定，一种 α2 肾上腺素受体激动剂， 当对吗啡耐受者进行鞘内给药时会产生镇痛作用 癌症患者。 这一发现对于治疗的重要性 由于药物替代方案很少，慢性疼痛很明显 目前可用于治疗阿片类药物耐受患者的疼痛。 更好地理解如何外源应用阿尔法 肾上腺素受体激动剂和内源性降去甲肾上腺素能系统 调节脊髓伤害性传导具有潜在的治疗作用 开发更具选择性和更有效的镇痛药的重要性 代理。