HYPOTHALAMUS AND NARCOTIC EFFECTS

下丘脑和麻醉作用

• 批准号: 3207438
• 负责人: HEMENDRA N BHARGAVA
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207438
• 关键词: analgesics; benzodiazepines; blood chemistry; brain metabolism; chordate locomotion; dopamine receptor; dosage; drug addiction antagonist; drug administration routes; drug adverse effect; drug metabolism; drug tolerance; drug withdrawal; hormone inhibitor; hypophysectomy; hypothalamic hormones; hypothalamus; hypothermia; laboratory mouse; laboratory rat; morphine; naloxone; narcotics; neuropeptide receptor; neuropeptides; opioid receptor; peptide hormone analog; radioimmunoassay; thyrotropin releasing hormone

The effect of potentially long acting and orally effective analogs of hypothalamic peptide hormones, particularly of melanotropin release inhibiting factor (MIF) and thyrotropin releasing hormone (TRH) on the acute (analgesia, hypothermia, etc.) and chronic effects (tolerance and physical dependence) of opiates, particularly of morphine, will be investigated in mice and rats. Tolerance to and physical dependence on morphine will be induced by the morphine pellet implantation procedure. Tolerance will be assessed by measuring the responses (e.g. analgesic, hypothermic, cataleptic, etc.) to varying doses of morphine in morphine and placebo pellet implanted animals. The degree of physical dependence will be measured by determining the intensity of signs like hypothermia, body weight loss, etc. during abrupt and naloxone-induced withdrawal and of stereotyped jumping, wet dog shakes, etc. during naloxone-induced withdrawal. The mechanism by which the peptides modify opiate tolerance-dependence process will be investigated by examining the functions of brain receptors for dopamine (D1 and D2), opiate (Mu, Delta and Kappa), MIF and TRH. This will be studied by the binding of 3H-ligands to membranes prepared from whole brain and brain regions. In addition, the effect of chronic administration of morphine on the concentration of enkephalins (to be determined by radioimmunoassay) and the activity of enkephalin degrading enzymes will be determined. Since studies in our laboratory have demonstrated for the first time that tifluadom, a Kappa opiate receptor agonist inhibits the binding of 3H-TRH to its receptors in the brain, further studies will be carried out with endogenous and exogenous ligands for Mu, Delta, and Kappa opiate receptors to understand these interactions. These studies may lead not only to understanding of the role of hypothalamic peptides in the chronic action of morphine but may also lead to the development of drugs that inhibit opiate addiction and manage the opiate induced distressing withdrawal syndrome.

潜在长效和口服有效的化合物的类似物的作用 下丘脑肽激素，特别是促黑素释放的肽激素 抑制因子（MIF）和促甲状腺激素释放激素（TRH）对 急性（镇痛、体温过低等）和慢性影响（耐受性和 阿片类药物，特别是吗啡的身体依赖性），将是 在小鼠和大鼠中进行了研究。 耐受和身体依赖 吗啡将通过吗啡丸粒植入程序诱导。 将通过测量反应（例如镇痛剂， 体温过低、僵硬等）不同剂量的吗啡 植入安慰剂颗粒的动物。 身体依赖的程度将 通过确定体温过低，身体 突然和纳洛酮诱导戒断期间的体重减轻等，以及 在纳洛酮诱导期间出现刻板跳跃、湿狗抖动等 戒断 多肽修饰阿片的机制 将通过检查 多巴胺（D1和D2）、阿片（Mu，Delta） 和Kappa）、MIF和TRH。 这将通过3 H-配体的结合来研究 到从整个大脑和大脑区域制备的膜。 此外该 吗啡长期给药对大鼠脑内 脑啡肽（通过放射免疫测定）和 将测定脑啡肽降解酶。 由于我们的研究 实验室首次证明， 阿片受体激动剂抑制3 H-TRH与其受体的结合， 大脑，进一步的研究将进行内源性和 Mu、Delta和Kappa阿片受体的外源性配体，以了解 这些互动。 这些研究可能不仅有助于理解 下丘脑肽在吗啡慢性作用中的作用，但可能 也导致了抑制鸦片成瘾的药物的开发， 治疗阿片类药物引起的痛苦戒断综合征