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.

动物暴露于应激刺激下会激活内源性 导致镇痛反应的机制，其中一些是介导的 通过中枢神经系统（CNS）。 取决于事物的性质 刺激和暴露参数，两种类型的压力引起 镇痛反应可由中枢神经系统引起：阿片类药物和非阿片类药物。 在 与阿片类药物介导的反应相比，非阿片类药物的反应不会被阻止 通过阿片拮抗剂，不会对重复暴露产生耐受性 应激源，并且与吗啡镇痛不表现出交叉耐受性。 迄今为止，非阿片类镇痛的介质尚未确定。 干扰脑组胺（HA）合成的药物及药物 阻断大脑 HA H2 受体的药物会抑制这种反应，而 直接注射到大脑中时，刺激 H2 受体会产生镇痛作用。 因为最近在 CNS 神经元中发现了 HA，并且相信 作为一个发射器，这些发现表明大脑 HA 是一个 非阿片类镇痛机制的介质。 本次活动的长期目标 项目旨在鉴定介导非阿片类药物的含 HA 细胞 应激诱导镇痛，绘制介导这些镇痛的途径 反应，以神经化学方式表征这些机制 药理学，并开发通过作用的新型镇痛剂 组胺能机制。 目前，几类药物的影响 与HA代谢和HA受体相关的药物将在阿片类药物上进行研究 和非阿片足电击诱导镇痛 (FSIA) 来进一步表征 HA 在 FSIA 中的作用。 几个实验将确定解剖学 HA 释放构成非阿片类镇痛途径一部分的位点： a) H2-拮抗剂西咪替丁的水平将以离散的方式测量 不同剂量的外周给药药物后中枢神经系统的区域， b) 垂体切除术、肾上腺切除术、脊柱切除术和 中丘去大脑将在 HA 介导的 FSIA 上确定， c) 脑室内、鞘内和脑内的影响 西咪替丁的注射将根据非阿片类 FSIA 确定。 到 探讨FSIA与脑神经化学指标的关系 HA，各种足部休克疗法的效果将取决于 HA 及其代谢物的水平，以及离散的 HA 周转率 大脑和脊髓区域。 这些研究是必要的 将 HA 描述为非阿片类镇痛介质，并可能导致 开发中枢作用的非阿片类镇痛药。