HISTAMINERGIC MECHANISMS OF ANALGESIA

组胺能镇痛机制

• 批准号: 3208515
• 负责人: LINDSAY HOUGH
• 金额: $ 21.17万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3208515
• 关键词: analgesics; antihistamines; brain mapping; brain metabolism; centrally acting drug; cimetidine; dosage; drug addiction antagonist; drug administration routes; drug metabolism; histamine receptor; laboratory rat; microinjections; morphine; naloxone; neurochemistry; neuropharmacology; neurotransmitter receptor; pain; radiotracer; stimulant /agonist

The neurotransmitter histamine (HA) causes analgesia when administered directly into the various brain areas, including the periaqueductal grey (PAG), an important site of action of morphine (MOR). Recent studies from this lab show that: 1) HA H2 receptor antagonists attenuate MOR analgesia, and 2) MOR enhances brain HA turnover, consistent with the hypothesis that activation of brain H2 receptors is important in the expression of MOR analgesia. The present proposal will clarify the role of histaminergic neurons in analgesic responses, and will identify the sites and mechanisms of action of HA-related drugs on these responses. To test directly the hypothesis that activation of brain H2 receptors is important for the expression of MOR analgesia, intraventricular (ivt) does-response curves will be determined for 11 H2 antagonists (of varying chemical structure and H2 potency) as inhibitors of MOR analgesia. The H2 antagonist cimetidine potentiates, rather than inhibits Mor analgesia; it will also be determined if this effect is a result of this drug's documented ability to inhibit MOR metabolism. To identify the CNS site (s) where H2 antagonists act to inhibit MOR analgesia, the effects of combinations of intracerebral, intrathecal and systemic administration of H2 antagonists and MOR will be studied. To pharmacologically classify the analgesia elicited by ivt and intracerebral HA, the effects of HA agonists (alone) and antagonists (in the presence of HA) will be assessed on antinociceptive responses. To determine the anatomical and pharmacological relationship(s) between histaminergic and opiate analgesia, the effects of acute and chronic combinations of HA and MOR will be determined. To characterize the neurochemical effects of MOR on brain HA dynamics, the actions of systemic MOR will be assessed on the levels and turnover of HA and its metabolites in brain regions and spinal cord. To learn the relationship between MOR analgesia and MOR's actions on HA turnover, pharmacological and microinjection experiments with MOR and HA turnover will be performed. To test the hypothesis that agents capable of altering histaminergic activity should modify analgesic responses, the effects of drugs that modify HA synthesis, HA metabolism, and neuronal HA release will be determined on antinociceptive tests in the presence and absence of MOR. These studies will enhance our knowledge of antinociceptive mechanisms, and may lead to the development of novel, clinically useful agents for the relief of pain.

神经递质组胺 (HA) 服用后会产生镇痛作用 直接进入各个大脑区域，包括导水管周围灰质 (PAG)，吗啡 (MOR) 的重要作用位点。最近的研究来自 该实验室表明：1) HA H2 受体拮抗剂会减弱 MOR 镇痛作用， 2) MOR 增强大脑 HA 更新，与以下假设一致： 脑H2受体的激活对于MOR的表达很重要 镇痛。本提案将阐明组胺能的作用 镇痛反应中的神经元，并将识别其位点和机制 HA 相关药物对这些反应的作用。直接测试 假设大脑 H2 受体的激活对于 MOR 镇痛、心室内 (ivt) 剂量反应曲线的表达 将确定 11 种 H2 拮抗剂（具有不同的化学结构和 H2 效力）作为 MOR 镇痛抑制剂。 H2拮抗剂西咪替丁 增强而不是抑制 Mor 镇痛；也将被确定 如果这种效应是该药物抑制 MOR 能力的结果 代谢。确定 H2 拮抗剂作用的 CNS 位点 抑制MOR镇痛，脑内组合的作用， H2拮抗剂和MOR的鞘内和全身给药将 研究过。对 ivt 引起的镇痛进行药理学分类 脑内HA，HA激动剂（单独）和拮抗剂（在 HA 的存在）将根据抗伤害反应进行评估。到 确定之间的解剖学和药理学关系 组胺能和阿片类镇痛，急性和慢性的影响 HA 和 MOR 的组合将被确定。来表征 MOR 对大脑 HA 动态、全身系统作用的神经化学影响 MOR 将根据 HA 及其代谢物的水平和周转率进行评估 在大脑区域和脊髓。了解MOR之间的关系 镇痛和 MOR 对 HA 周转、药理学和 将进行 MOR 和 HA 转换的显微注射实验。到 检验能够改变组胺能活性的药物的假设 应该改变镇痛反应，改变HA的药物的作用 合成、HA 代谢和神经元 HA 释放将取决于 在存在和不存在 MOR 的情况下进行抗伤害测试。这些研究 将增强我们对抗伤害机制的了解，并可能导致 开发新型的、临床上有用的缓解疼痛的药物。