TOLERANCE TO DRUGS: MUCOUS GLAND CELL FUNCTION

药物耐受性：粘液腺细胞功能

• 批准号: 3211130
• 负责人: Jerry M. Farley
• 金额: $ 10.43万
• 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/3211130
• 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.

本申请的长期目标是获得良好的 了解生理学和药理学的功能 粘液和液体分泌在气道无论是在正常和疾病 states. 可卡因是一种主要的滥用药物， 通过鼻子吸入可卡因粉末或吸烟 自由基。 这意味着鼻粘膜组织和 上呼吸道将急性暴露于高浓度的 这个特工。 因此，这种药物既可以作为局部麻醉剂， 拟交感神经药物将导致神经系统功能的变化。 肌下腺细胞 此外，可卡因通常 而那些使用它的人，也可能会重复使用它。 在较长的时间内服用它可能会变得宽容， 它的行动。 该提案旨在确定正常的 刺激，诱导分泌液体和粘液， 肌下腺细胞 然后用这些知识来确定 可卡因的急性和慢性影响 功能正常的粘膜下腺细胞 的性质 将从断奶猪分离的肌下腺细胞， 通过使用酶从粘膜分离细胞来确定， 随后进行使用密度梯度的纯化步骤。 细胞 然后将用于放射性配体结合测定，以确定 肾上腺素能和毒蕈碱受体的特性 以及这些特征是如何 改变了可卡因暴露。 二是生理功能 将通过测量神经递质和 神经诱发的粘液分泌和氯化物通量。 的影响 将确定可卡因对这些功能的影响。 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。 的 可卡因阻断或以其他方式相互作用的能力， 将确定离子通道。 慢性病的影响 可卡因暴露对猪粘膜下腺功能的影响 细胞也将被确定。 猪将通过鼻内途径暴露 每天2 - 3次施用可卡因粉末，持续7天。 腺体的药理生理特性 然后通过上面给出的方法确定细胞功能。 慢性可卡因暴露对粘膜下腺细胞的影响 还将在利血平预处理的猪中检查功能 耗尽外周的儿茶酚胺储备 这将允许一个 研究可卡因在没有其" 拟交感神经作用