HISTAMINERGIC MECHANISMS OF NON-OPIATE ANALGESIA

动物暴露于压力刺激激活内源性 导致镇痛反应的机制，其中一些是介导的 中枢神经系统（CNS）。 取决于 刺激和暴露参数，两种类型的应激诱导 镇痛反应可由CNS引起：阿片剂和非阿片剂。 在 与阿片类药物介导的反应相反，非阿片类药物反应不被阻断， 通过阿片拮抗剂，不会对重复暴露产生耐受性 应激源，并没有表现出交叉耐受与吗啡镇痛。 到目前为止，非阿片类镇痛介质尚未确定。 干扰脑组织胺（HA）合成的药物和药物 阻断大脑HA H2受体的药物抑制这种反应，而 刺激H2-受体当直接注射到脑中时引起镇痛。 因为最近在CNS神经元中鉴定出HA， 这些发现表明，大脑HA是一种 非阿片类镇痛机制的介质。 长期目标是 项目是确定含有HA的细胞介导的非阿片类药物 应激诱导的镇痛，以映射介导这些镇痛的途径， 反应，以表征这些机制的神经化学和 并开发新的镇痛剂， 组胺能机制 目前，几种类型的影响 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， 和非阿片类药物足震诱导的镇痛（FSIA），以进一步表征 医管局在FSIA中的角色。 几个实验将确定解剖 HA释放包含部分非阿片类镇痛剂途径的部位： a）H2-拮抗剂西咪替丁的水平将以不连续的方式测量， 在不同剂量的外周给药药物后的CNS区域， B）垂体切除术、肾上腺切除术、脊柱切除术和 将在HA介导的FSIA上确定中丘去脑， 和c）脑室内、鞘内和脑内的作用 西咪替丁注射将在非阿片FSIA上确定。 到 探讨FSIA与脑神经化学指标的关系 医管局将根据 水平的HA及其代谢物，并对HA周转率在离散 大脑和脊髓的区域。 这些研究对于 将HA表征为非阿片类镇痛的介质，并可能导致 开发中枢作用的非阿片类镇痛剂。

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.