HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述：（申请人摘要） 阿片类镇痛药吗啡（莫尔）已被证明可以通过以下方式缓解疼痛： 包括释放神经元组胺（HA）和 随后激活中脑导水管周围灰质（PAG）中的HA受体。 HA 已知在中枢神经系统中作为神经调节物质起作用 系统 拟议的研究将通过以下方式描述部位和机制： HA缓解疼痛，并寻找新的缓解疼痛的药物， 基于这些机制。 这些实验将使用的技术， 体内微透析，脑内注射，和伤害性测试， 大鼠 将进行以下研究：1）莫尔增加 PAG中神经元HA的释放。 为了确定这一机制， 选择性阿片受体激动剂和拮抗剂的作用 将在体内研究PAG中HA的释放。 2)HA注射 进入PAG诱导疼痛缓解（即镇痛）反应，并且在较高的 剂量，疼痛增强（即痛觉过敏）反应。 来发现 HA诱导的伤害性变化的药理学机制 阈值，选择性HD激动剂和HA拮抗剂的作用将是 在脑内给药至PAG后进行研究。 独特的HA样 还将研究化合物SKF 92374，因为该药剂似乎诱导 镇痛，但不是痛觉过敏反应，由以前未发现的 机制 3)HA和莫尔相互作用产生协同镇痛作用 应答 为了描述这些相互作用的性质，定量 抗伤害性研究将用各种剂量的组合进行 HA和莫尔。 此外，选择性拮抗剂的作用， 阿片受体和HA受体的亚型将在这些方面进行研究。 在这些MOR-HA组合的存在下的反应。 除了 这些PAG的研究，试点研究表明，HA也可能是一种 在中缝大肌（RM，另一个脑干）的抗伤害性介质 已知在疼痛缓解中重要的结构）。 为了解决这个 假设，上述为PAG提出的几个实验也将 在RM中执行。 这些研究将阐明 莫尔缓解疼痛，增强对组胺能 抗伤害机制，并可能导致发现非成瘾， 用于治疗疼痛的新药物。

DESCRIPTION: (Applicant's Abstract) The opiate analgesic drug morphine (MOR) has been shown to relieve pain by mechanisms that include the release of neuronal histamine (HA) and the subsequent activation of HA receptors in the periaqueductal grey (PAG). HA is known to function as a neuromodulator substance in the central nervous system. The proposed studies will characterize the sites and mechanisms by which HA relieves pain, and search for novel, pain-relieving medications based on these mechanisms. The experiments will use the techniques of in vivo microdialysis, intracerebral injections, and nociceptive testing in rats. The following studies will be performed: 1) MOR increases the release of neuronal HA in the PAG. To determine the mechanisms of this response, the effects of selective opiate receptor agonists and antagonists will be studied on the release of HA in the PAG in vivo. 2) HA injections into the PAG induce pain-relieving (i.e. analgesic) responses and, at higher doses, pain-enhancing (i.e. hyperalgesic) responses. To discover the pharmacological mechanisms underlying the HA-induced changes in nociceptive threshold, the effects of selective HD agonists and HA antagonists will be studied after intracerebral administration into the PAG. The unique HA-like compound SKF92374 will also be studied, since this agent appears to induce analgesic, but not hyperalgesic responses by a previously undiscovered mechanism. 3) HA and MOR interact to produce synergistic analgesic responses. To characterize the nature of these interactions, quantitative antinociceptive studies will be performed with combinations of various doses of HA and MOR. In addition, the effects of antagonists selective for sub-types of opiate receptors and HA receptors will be studied on these responses in the presence of these MOR-HA combinations. In addition to these studies of the PAG, pilot studies suggest that HA may also be an antinociceptive mediator in the raphe magnus (RM, another brain stem structure known to be important in pain relief). To address this hypothesis, several of the experiments proposed above for the PAG will also be performed in the RM. These studies will clarify the mechanisms by which MOR relieves pain, enhance the understanding of histaminergic antinociceptive mechanisms, and may lead to the discovery of non-addicting, novel medications for the treatment of pain.