HISTAMINERGIC MECHANISMS OF ANALGESIA

神经递质组胺(HA)给药时会产生止痛作用。 直接进入不同的大脑区域，包括中脑导水管周围灰质 (PAG)，吗啡(MOR)的重要作用部位。最近来自 本实验表明：1)HA H_2受体拮抗剂可减弱吗啡的镇痛作用， 2)MOR可增加脑内HA的周转，这与假设一致 大脑H2受体的激活在MOR的表达中起重要作用 止痛药。本提案将阐明组胺能的作用 神经元在镇痛反应中的作用，并将确定其部位和机制 与HA相关的药物对这些反应的作用。要直接测试 假设大脑H2受体的激活对 吗啡镇痛、脑室内给药剂量-反应曲线的表达 将被确定为11种氢拮抗剂(化学结构和 H2效价)作为吗啡镇痛的拮抗剂。H2拮抗剂西咪替丁 增强而不是抑制吗啡的止痛；它也将被确定 如果这种效果是这种药物抑制吗啡的已知能力的结果 新陈代谢。确定H2拮抗剂作用的中枢神经系统部位(S) 抑制吗啡镇痛，脑内联合用药的效果， 鞘内和全身给予H2拮抗剂和MOR 学习。对静脉注射和静脉注射的镇痛作用进行药理学分类 脑内HA，HA激动剂(单独)和拮抗剂(In HA的存在将根据抗伤害性反应进行评估。至 确定两者之间的解剖和药理关系(S) 组胺能和阿片类镇痛对急性和慢性的影响 HA和MOR的组合将被确定。要刻画 吗啡对脑透明质酸动力学、全身性活动的神经化学影响 MOR将根据HA及其代谢物的水平和周转进行评估 在大脑区域和脊髓。要了解更多信息之间的关系 镇痛和吗啡对透明质酸代谢、药理和免疫功能的影响 将进行MOR和HA周转率的显微注射实验。至 验证能够改变组胺能活性的药物的假设 应该修改止痛反应，修改HA的药物的效果 合成、HA代谢和神经元HA释放将在 在MOR存在和不存在的情况下进行的抗伤害反应试验。这些研究 将增强我们对抗伤害性感受机制的了解，并可能导致 开发新的、临床上有用的止痛剂。

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.