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

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 最近发现的止痛药物与以下化学物质有关 组胺。 原型机（命名为improgan）具有以下特点 直接注射到啮齿动物大脑后：a) 非常有效， 热和机械测试中的吗啡样镇痛作用，b) 无损害 运动协调或运动活动，c）非阿片类机制 独立于已知的组胺受体和 60 个其他靶标，d) 缺乏 每日给药的耐受性，以及 e) 独特的结构-活性关系 在化学同系物中，表明可能存在一种新的 组胺受体。 然而，人们对于其位点和机制知之甚少。 improgan 的行动。 为了解决这些问题，将进行以下研究 在大鼠中进行。 1) 显微注射图研究将识别中枢神经系统 介导 improgan 镇痛的区域。 已知包含内源性的位点 将研究疼痛缓解系统（导水管周围灰质、吻侧 腹侧延髓[包括中缝大核]和脊髓）。 2） 这些显微注射的效果将通过两种运动测量来评估 功能（旋转杆测试和运动活动）来评估特异性 英普甘镇痛。 3) 递质激动剂的显微注射研究和 拮抗剂将识别脊髓上和脊髓递质机制 介导improgan镇痛。 4）两种实验将搜索 improgan 受体：a) improgan 诱导的 35S-GTPgammaS 调节 将研究脑膜中的结合，并且 b) 匀浆并 放射自显影技术将研究放射性标记衍生物的结合 的improgan。 这些研究也可能有助于开发一种体外检测方法 类似improgan的活动。 5) 确定improgan类镇痛药是否有效 在人类炎症性疼痛的临床前模型中有效， improgan 将在大鼠福尔马林伤害性试验中进行研究。 这 拟议的实验将表征基本神经元机制 非阿片类镇痛，并可能导致新组胺的发现 受体，和/或开发新的药物疗法来治疗急性和 慢性疼痛。