HISTAMINERGIC MECHANISMS OF ANALGESIA

神经递质组胺（HA）给药时引起镇痛 直接进入大脑的各个区域，包括中脑导水管周围灰质 (PAG)是吗啡（莫尔）的重要作用部位。最近的研究来自 本实验表明：1）HA H2受体拮抗剂减弱莫尔镇痛， 和2）莫尔增强脑HA周转，与以下假设一致： 脑H2受体的激活在莫尔的表达中是重要的 analgesia.目前的建议将阐明组胺能神经递质的作用。 神经元的镇痛反应，并将确定网站和机制 HA相关药物对这些反应的作用。直接测试 假设大脑H2受体的激活对于 莫尔镇痛的表达，室内（ivt）剂量-反应曲线 将确定11种H2拮抗剂（化学结构不同， H2效力）作为莫尔镇痛的抑制剂。H2拮抗剂西咪替丁 增强而不是抑制莫尔镇痛;它也将被确定 如果这种作用是由于该药物抑制莫尔的能力 新陈代谢.确定H2拮抗剂作用的CNS部位， 抑制莫尔镇痛，脑内， H2拮抗剂和莫尔的鞘内和全身给药将 研究了对ivt镇痛作用进行分类， 脑内HA，HA激动剂（单独）和拮抗剂（在 HA的存在）将根据抗伤害感受反应进行评估。到 确定以下之间的解剖学和药理学关系 组胺能和阿片类镇痛，急性和慢性的影响， 将确定HA和莫尔的组合。表征 莫尔对脑HA动力学的神经化学作用，全身性 莫尔将根据HA及其代谢产物的水平和转换进行评估 在大脑区域和脊髓中。为了了解莫尔与 镇痛和莫尔对HA周转的作用，药理学和 将进行具有莫尔和HA周转的显微注射实验。到 检验能够改变组胺能活性的药物 应该改变镇痛反应，改变HA的药物的作用， HA合成、HA代谢和神经元HA释放将在 在存在和不存在莫尔的情况下的抗伤害感受试验。这些研究 将增强我们对抗伤害机制的了解，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.