HISTAMINERGIC MECHANISMS OF NON-OPIATE ANALGESIA

非阿片类镇痛的组胺能机制

• 批准号: 3208513
• 负责人: LINDSAY HOUGH
• 金额: $ 16.83万
• 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 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3208513
• 关键词: adrenalectomy; analgesics; antihistamines; barbiturates; brain mapping; brain metabolism; centrally acting drug; chordate locomotion; cimetidine; decerebration; dosage; drug addiction antagonist; drug administration routes; drug design /synthesis /production; drug metabolism; enzyme mechanism; gas chromatography; genetic strain; histamine; histamine receptor; hypophysectomy; laboratory rat; mass spectrometry; mast cell; monoclonal antibody; morphine; naloxone; neurochemistry; neuropharmacology; neurotransmitter metabolism; neurotransmitter receptor; pentobarbital; radiotracer; spinal cord surgery

The exposure of animals to stressful stimuli activates endogenous mechanisms that result in analgesic responses, some of which are mediated by the central nervous system (CNS). Depending on the nature of the stimulus and the parameters of exposure, two types of stres-induced analgesic responses can be elicited by the CNS: opiate and non-opiate. In contrast to opiate-mediated responses, non-opiate responses are not blocked by opiate antagonists, do not develop tolerance to repeated exposures of the stressor, and do not exhibit cross-tolerance with morphine analgesia. Thus far, the mediators of non-opiate analgesia have not been identified. Drugs that interfere with the synthesis of brain histamine (HA) and drugs that block brain HA H2-receptors inhibit this response, whereas drugs that stimulate H2-receptors cause analgesia when injected directly into brain. Because HA has been recently identified within CNS neurons and is believed to function as a transmitter, these finding suggest that brain HA is a mediator of non-opiate analgesic mechanisms. The long-term goals of this project are to identify the HA-containing cells mediating non-opiate stress-induced analgesia, to map the pathways mediating these analgesic responses, to characterize these mechanisms neurochemically and pharmacologically, and to develop novel analgesic agents that act through histaminergic mechanism. Presently, the effects of several classes of drugs related to HA metabolism and HA receptors will be studied on opiate- and non-opiate footshock-induced analgesia (FSIA) to characterize further the role of HA in FSIA. Several experiments will identify the anatomical site where HA release comprises part of the non-opiate analgesic pathway: a) the levels of the H2-antagonist cimetidine will be measured in discrete regions of the CNS after various doses of peripherally-administered drug, b) the effects of hypophysectomy, adrenalectomy, spinalectomy and mid-collicular decerebration will be determined on the HA-mediated FSIA, and c) the effects of intraventricular, intrathecal, and intracerebral injections of cimetidine will be determined on the non-opiate FSIA. To explore the relationship between FSIA and neurochemical indices of brain HA, the effects of various regimens of footshock will be determined on the levels of HA and its metabolite, and on HA turnover rates in discrete regions of brain and spinal cord. These studies are necessary to characterize HA as a mediator of non-opiate analgesia, and may lead to the development of centrally-acting non-opiate analgesic agents.

动物暴露于压力刺激会激活内源性 导致镇痛反应的机制，其中一些是介导的 由中枢神经系统（CNS）。 取决于 刺激和暴露参数，两种类型的Stres诱导 CNS可以引起镇痛反应：鸦片和非焦点。 在 与鸦片介导的响应形成鲜明对比，非伴随响应不会被阻止 通过鸦片拮抗剂，请勿对重复暴露的容忍度 压力源，并且不与吗啡镇痛表现出跨耐受性。 到目前为止，尚未确定非伴侣镇痛的介体。 干扰脑组胺（HA）和药物合成的药物 阻止大脑H2受体抑制这种反应，而药物则是 当直接注入大脑时，刺激H2受体会引起镇痛。 因为HA最近在中枢神经系统神经元中被鉴定出来，并且被认为 这些发现充当发射器，表明大脑HA是一个 非型镇痛机制的介体。 这个长期目标 项目将确定介导非焦点的含HA的细胞 应力诱导的镇痛，以绘制介导这些镇痛的途径 响应，以神经化学和 从药理上，开发通过起作用的新型镇痛药 组胺能机制。 目前，几类的影响 与HA代谢和HA受体有关的药物将在阿片类药物上进行研究 和非运动脚印引起的镇痛（FSIA）以进一步表征 HA在FSIA中的作用。 几个实验将识别解剖学 HA释放的位置包括一部分非聚体镇痛途径： a）将在离散的 各种剂量的外围药物后，中枢神经系统的区域， b）下生理切除术，肾上腺切除术，脊柱切除术和 典型的解剖将在HA介导的FSIA上确定， c）脑室内，鞘内和脑内脑内的影响 将在非伴侣FSIA上确定甲己丁定的注射。 到 探索FSIA与大脑神经化学指标之间的关系 ha，将确定各种脚印的影响对 HA及其代谢产物的水平以及离散的HA离职率 大脑和脊髓的区域。 这些研究是必要的 将HA描述为非型镇痛的介体，并可能导致 中心作用的非运动镇痛药的发展。