HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

组胺能抗伤害机制

• 批准号: 6515371
• 负责人: LINDSAY HOUGH
• 金额: $ 31万
• 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 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515371
• 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; analgesics; antihistamines; drug interactions; drug metabolism; histamine; histamine receptor; hyperalgesia; laboratory rat; microdialysis; morphine; neuropharmacology; opioid receptor; periaqueductal gray matter; pons; stimulant /agonist

DESCRIPTION (adapted from applicant's abstract): A new class of non-opioid pain-relieving drugs has recently been discovered that is chemically related to histamine. The prototype (named improgan) shows the following characteristics after direct injection into the rodent brain: a) highly effective, morphine-like antinociception on thermal and mechanical tests, b) no impairment of motor coordination or locomotor activity, c) a non-opioid mechanism that is independent of known receptors for histamine and 60 other targets, d) lack of tolerance with daily dosing, and e) unique structure-activity relationships among chemical congeners, suggesting the possible existence of a novel histamine receptor. However, little is known about the sites and mechanisms of action of improgan. To approach these issues, the following studies will be performed in rats. 1) Microinjection mapping studies will identify the CNS areas mediating improgan analgesia. Sites known to comprise the endogenous pain-relieving system will be studied (the periaqueductal grey, the rostral ventral medulla [including the nucleus raphe magnus] and the spinal cord). 2) The effects of these microinjections will be assessed on two measures of motor function (rotorod test and locomotor activity) to assess the specificity of improgan analgesia. 3) Microinjection studies with transmitter agonists and antagonists will identify the supraspinal and spinal transmitter mechanisms that mediate improgan analgesia. 4) Two kinds of experiments will search for the improgan receptor: a) the improgan-induced modulation of 35S-GTPgammaS binding in brain membranes will be studied, and b) homogenate and autoradiography techniques will study the binding of a radiolabeled derivative of improgan. These studies may also help to develop an in vitro assay for improgan-like activity. 5) To determine if improgan-like analgesics are effective in preclinical models of human inflammatory pain, the activity of improgan will be studied in the formalin nociceptive test in rats. The proposed experiments will characterize the fundamental neuronal mechanisms of non-opioid analgesia, and may lead to the discovery of a new histamine receptor, and/or to the development of new pharmacotherapies for acute and chronic pain.

描述（改编自申请人的摘要）：一类新的非阿片类药物 最近发现疼痛的药物与 组胺。 原型（命名为Impogan）显示以下特征 直接注入啮齿动物大脑后：a）高效， 热和机械测试上的吗啡样抗伤害感受，b）无损害 运动协调或运动活性的 独立于组胺的已知受体和其他60个靶标，d）缺乏 每日给药的耐受性，e）独特的结构活性关系 在化学同源物中，表明可能存在新颖的 组胺受体。 但是，关于地点和机制知之甚少 Impogan的动作。 要解决这些问题，以下研究将是 在大鼠中进行。 1）显微注射映射研究将确定中枢神经系统 介导不镇痛的区域。 已知包括内源性的站点 将研究疼痛的系统（周围灰色，the骨 腹侧髓质[包括核raphe Magnus]和脊髓）。 2） 这些显微注射的影响将在两个措施的电动机上评估 功能（Rotorod测试和运动活动）以评估 Improgan镇痛。 3）发射器激动剂和 拮抗剂将识别上脊髓和脊柱发射器机制 介导不镇痛。 4）两种实验将搜索 Impogan受体：a）35S-GTPGAMMAS的Imbogan诱导的调节 将研究脑膜中的结合，b）匀浆和 放射自显影技术将研究放射性标记的衍生物的结合 Impogan。 这些研究也可能有助于开发用于的体外测定法 类似的活动。 5）确定不适的镇痛药是否是 在人类炎症性疼痛的临床前模型中有效 将在大鼠的福尔马林伤害感受性测试中进行研究。 这 提出的实验将表征基本的神经元机制 非阿片类镇痛，可能导致发现新组胺 受体和/或开发新的急性药物疗法 慢性疼痛。