HISTAMINERGIC MECHANISMS OF NON-OPIATE ANALGESIA

动物暴露在应激性刺激下会激活内源性 导致止痛反应的机制，其中一些是由 由中枢神经系统(CNS)控制。视情况而定 刺激和暴露参数，两种类型的应激诱导 中枢神经系统：阿片剂和非阿片剂均可引起镇痛反应。在……里面 与阿片剂介导的反应不同，非阿片剂反应不会被阻断 通过阿片类拮抗剂，不会对反复暴露于 应激源，且与吗啡镇痛不表现出交叉耐受。 到目前为止，非阿片类镇痛的介体还没有确定。 干扰脑组胺(HA)合成的药物和药物 阻断大脑透明质酸H2受体抑制这种反应，而药物 当直接注射到大脑中时，刺激H2受体会产生止痛作用。 因为最近在中枢神经系统神经元中发现了HA，并被认为 作为一种递质，这些发现表明大脑HA是一种 非阿片类止痛机制的中介物。这样做的长期目标是 项目是确定含有HA的细胞介导非阿片类药物 应激诱导的镇痛，以绘制这些止痛剂的中介通路 反应，以神经化学和 药理作用，并开发新的止痛剂，通过 组胺能机制。目前，几个类别的效果 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 和非阿片类足底电击诱导镇痛(FSIA)的进一步特征 透明质酸在FSIA中的作用。几个实验将确定解剖学上 HA释放包括部分非阿片类止痛途径的部位： A)H2-拮抗剂西咪替丁的水平将以离散的方式测量 在不同剂量的外周给药后， B)垂体切除、肾上腺切除、脊髓切除和 将在HA介导的FSIA上确定丘中去大脑， 以及c)脑室、鞘内和脑内的影响 西咪替丁的注射将在非阿片类FSIA上确定。至 FSIA与脑内神经化学指标关系的探讨 哈，不同的足击方案的效果将在 体内HA及其代谢物水平及对HA周转率的影响 大脑和脊髓的区域。这些研究是必要的，以 将HA定性为非阿片类镇痛的介体，并可能导致 中枢作用非阿片类止痛药的开发。

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.