TOLERANCE TO DRUGS: MUCOUS GLAND CELL FUNCTION

药物耐受性：粘液腺细胞功能

• 批准号: 3211131
• 负责人: Jerry M. Farley
• 金额: $ 11.07万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3211131
• 关键词: adrenergic agents; adrenergic receptor; central nervous system stimulants; cocaine; density gradient ultracentrifugation; drug tolerance; electrical measurement; inhalation drug abuse; ion transport; local anesthetics; mucus; muscarinic receptor; oral mucosa; secretion; swine; weanling animal

The long term objective of this application is to gain a good understanding of the physiology and pharmacology of the function of mucus and fluid secretion in airways both in normal and disease states. Cocaine is a major drug of abuse which is taken primarily by inhalation of cocaine powder through the nose or by smoking the free-base. This means that the mucosal tissue of the nose and upper airways will be acutely exposed to high concentrations of this agent. Thus this drug either as a local anesthetic or as a sympathomimetic agent will lead to changes in the function of the submuscosal gland cells. In addition cocaine is generally taken repeatedly by those who use it. Thus, it may be that those who take it over an extended period of time may become tolerant to its action. This proposal is designed to determine the normal stimuli which induce the secretion of fluid and mucus from submuscosal gland cells. Then with this knowledge to determine what the acute and chronic effects of cocaine are on the functioning submuscosal gland cells. the properties of submuscosal gland cells isolated from weanling swine will be determined by isolating the cells from the mucosa using enzymes, followed by a purification step using density grandients. The cells will then be used in radioligand binding assays to determine the characteristics of the adrenergic and muscarinic receptors present on these cells and how these characteristics may be changed by cocaine exposure. Second the physiological function of the cells will be assayed by measuring neurotransmitter and neurally evoked mucus secretion adn chloride flux. The effect of cocaine on these functions will be determined. Finally, the effects of cocaine on the properties of ion channels in the tissue will be determined by use of the patch clamp technique. The ability of cocaine to block, or interact in other ways, with the ionic channels will be determined. The effects of chronic exposure of swine to cocaine on the function of submucosal gland cells will also be determined. Swine will be exposed via intranasal application of cocaine powder 2-3 times daily for up to 7 days. The pharmacological and physiological characteristics of gland cell function will then be determined by the methods given above. The effects of chronic cocaine exposure on submucosal gland cell function will also be examined in swine pretreated with reserpine to deplete peripheral catecholamine stores. This will permit an examination of the action of cocaine in the absence of its' sympathomimetic action.

这项应用的长期目标是获得良好的 对功能的生理学和药理学的认识 正常和疾病患者的呼吸道粘液和液体分泌物 各州。可卡因是一种主要的滥用药物，主要服用 通过鼻子吸入可卡因粉末或吸烟 自由垒。这意味着鼻部和鼻部的粘膜组织 上呼吸道会剧烈地暴露在高浓度的 这位特工。因此，这种药物既可以作为局部麻醉剂，也可以作为 拟交感神经诱导剂会导致神经细胞功能的改变 肌下腺细胞。此外，人们通常服用可卡因 被那些使用它的人反复使用。因此，可能是那些 长时间服用可能会变得耐受 它的行动。本提案旨在确定正常的 引起液体和粘液分泌的刺激 肌下腺细胞。然后用这个知识来确定 可卡因的急性和慢性影响是什么？ 功能正常的肌下腺细胞。的属性 从断奶仔猪中分离的肌下腺细胞将 通过使用酶将细胞从粘膜中分离出来， 然后使用密度梯度进行纯化步骤。这些细胞 将用于放射性配基结合分析，以确定 肾上腺素能受体和M受体的特性 以及这些特征是如何存在的 因接触可卡因而改变。第二，生理功能 将通过测量神经递质和 神经诱发粘液分泌和氯化物流量。的影响 可卡因对这些功能的影响将被确定。最后， 可卡因对组织离子通道特性的影响 将通过使用膜片钳技术来确定。这个 可卡因能够阻止或以其他方式与 离子通道将被确定。慢性病的影响 猪暴露可卡因对粘膜下腺功能的影响 单元格也将被确定。猪只会通过鼻腔暴露 每日使用2-3次可卡因粉末，最多使用7天。 腺体的药理和生理特性 然后将通过上面给出的方法来确定单元函数。 慢性可卡因暴露对粘膜下腺细胞的影响 利血平预处理的猪的功能也将被检测。 以耗尽外周的儿茶酚胺储存。这将允许一个 在没有可卡因的情况下考察可卡因的作用 模仿交感神经的行为。