HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

组胺能抗伤害机制

• 批准号: 2012856
• 负责人: LINDSAY HOUGH
• 金额: $ 20.14万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2012856
• 关键词: analgesics; antihistamines; drug interactions; drug metabolism; histamine; histamine receptor; hyperalgesia; laboratory rat; microdialysis; morphine; neuropharmacology; opioid receptor; periaqueductal gray matter; pons; stimulant /agonist

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.

描述：（申请人的摘要） 鸦片镇痛药吗啡（MOR）已显示可缓解疼痛 包括神经元组胺（HA）和释放的机制 随后的灰灰色受体激活（PAG）。 哈 被称为中枢神经中的神经调节剂物质 系统。 拟议的研究将通过 这会缓解疼痛，并寻找新颖的，疼痛的药物 基于这些机制。 实验将使用IN的技术 体内微透析，脑内注射和伤害性测试 老鼠。 将进行以下研究：1）MOR增加 在PAG中释放神经元HA。 确定此机制 反应，选择性鸦片受体激动剂和拮抗剂的影响 将研究在体内释放HA的释放。 2）HA注射 进入PAG诱导疼痛扭曲（即镇痛）反应，在较高的情况下 剂量，增强疼痛（即高效应）反应。 发现 HA引起的伤害感受的药理机制 阈值，选择性高清激动剂和HA拮抗剂的影响将是 脑内给药后进行了研究。 独特的ha 还将研究复合SKF92374，因为该代理似乎诱导了 先前未被发现的止痛反应，但不是镇痛 机制。 3）HA和MOR相互作用以产生协同镇痛 回答。 为了表征这些相互作用的性质，定量 将与各种剂量的组合进行抗伤害感受性研究 哈和莫尔。 另外，拮抗剂选择性的影响 在这些方面将研究鸦片受体和HA受体的子类型 在存在这些MOR-HA组合的情况下的响应。 此外 这些对PAG的研究，试点研究表明，HA也可能是 Raphe Magnus中的抗伤害感受介质（RM，另一个脑干 已知在缓解疼痛中很重要的结构。 解决这个问题 假设，上述PAG上面提出的一些实验也将 在RM中执行。 这些研究将阐明 Mor减轻疼痛，增强对组胺能的理解 抗伤害感受机制，可能导致发现不添加的机制， 用于治疗疼痛的新型药物。