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：（申请人摘要） 阿片类镇痛药吗啡 (MOR) 已被证明可以通过以下方式缓解疼痛： 机制包括释放神经元组胺 (HA) 和 随后激活导水管周围灰质 (PAG) 中的 HA 受体。 哈 已知在中枢神经中起到神经调节物质的作用 系统。 拟议的研究将通过以下方式描述地点和机制的特征： 哪种HA可以缓解疼痛，并寻找新型止痛药物 基于这些机制。 实验将使用以下技术 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 PAG 中神经元 HA 的释放。 为了确定这一机制 反应，选择性阿片受体激动剂和拮抗剂的作用 将研究体内PAG中HA的释放。 2）HA注射 进入 PAG 会引起镇痛（即镇痛）反应，并且在较高浓度下 剂量、疼痛增强（即痛觉过敏）反应。 去发现 HA 引起的伤害感受变化的药理学机制 阈值时，选择性 HD 激动剂和 HA 拮抗剂的作用将是 脑内注射至 PAG 后进行研究。 独特的HA样 化合物 SKF92374 也将被研究，因为该药物似乎会诱导 以前未发现的镇痛反应，但不是痛觉过敏反应 机制。 3）HA和MOR相互作用产生协同镇痛作用 回应。 为了表征这些相互作用的性质，定量 将使用不同剂量的组合进行抗伤害研究 医管局和铁道部。 此外，拮抗剂的作用选择性 阿片受体和 HA 受体的亚型将在这些方面进行研究 这些 MOR-HA 组合存在时的反应。 此外 这些关于 PAG 的研究表明，HA 也可能是一种 中缝大肌（RM，另一个脑干）中的镇痛介质 已知对缓解疼痛很重要的结构）。 为了解决这个问题 假设，上面为 PAG 提出的几个实验也将 在 RM 中执行。 这些研究将阐明其机制 MOR缓解疼痛，增强对组胺能的认识 抗伤害机制，并可能导致发现非成瘾性， 用于治疗疼痛的新型药物。