Interdependence among neuromodulators of ventilatory control

通气控制神经调节剂之间的相互依赖性

• 批准号: 8703171
• 负责人: HUBERT V FORSTER
• 金额: $ 36.53万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703171
• 关键词: Adult; Agonist; Anesthesia procedures; Apnea; Attenuated; Blood gas; Brain Part; Breathing; Cell Nucleus; Cells; Cerebrospinal Fluid; Chemoreceptors; Complex; Depressed mood; Dialysis procedure; Equilibrium; Failure; Frequencies; Generations; Glycine; Goals; Goat; HTR2A gene; Homeostasis; Human; Implant; In Vitro; Lead; Measures; Microdialysis; Microtubules; Motor; Muscarinic Antagonists; Muscle; Neuromodulator; Neuromodulator Receptors; Neurons; Opiates; Opioid; Opioid Receptor; Overdose; Pain; Peripheral; Pharmaceutical Preparations; Pulmonary Ventilation; Pump; REM Sleep; Receptor Activation; Respiratory Diaphragm; Serotonin; Site; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Substance P; Substance P Receptor; Synapses; Testing; Ventilatory Depression; Wakefulness; awake; cholinergic; in vivo; neurochemistry; neuroregulation; public health relevance; receptor; respiratory; response

DESCRIPTION (provided by applicant): Neurons within the respiratory network initiate and coordinate respiratory pump and airway muscle activation to adjust the level of pulmonary ventilation ( I) to maintain blood gas homeostasis. Chemoreceptors provide major excitatory drives to breathe (19, 22, 31, 65, 82), but it is the overall balance of excitatory and inhibitory neuromodulators that ultimately determine respiratory network excitability (15, 16, 28, 92). The contribution of endogenous neuromodulators to eupneic I while awake or asleep has not been determined, but in vitro evidence suggests "that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators" (16). The overall goal of our proposal is to test this hypothesis of neuromodulatory interdependence and test whether inadequate interdependence contributes to sleep disordered breathing (SDB) and/or opiate overdose-induced respiratory depression. In adult goats, microtubules will be chronically implanted for insertion into the preB¿tzinger Complex (preB¿tC) or hypoglossal motor nucleus (HMN) of probes for dialysis in mock cerebral spinal fluid (mCSF) of antagonists or agonist of excitatory or inhibitory neuromodulators during awake and asleep states. We will measure I, diaphragm and genioglossus (GG) muscle activity, and neurochemicals in effluent dialyzed mCSF. Specific Aim 1 determines whether there is interdependence among multiple excitatory neuromodulators within the preB¿tC. We hypothesize that: a) antagonists of muscarinic cholinergic, serotonin (5-HT2A), or neurokinin-1 receptors individually will have little or no effet on eupneic I and GG muscle activity but in combination will attenuate I and GG activity particularly during sleep and lead to SDB, b) antagonists of excitatory neuromodulatory inputs to the preB¿tC will produce compensatory changes in other neuromodulators at the site of antagonist dialysis. Specific Aim 2 determines whether there is interdependence within the preB¿tC between excitatory neuromodulators and the inhibitory neuromodulatory effects of ¿-opioid receptor activation. We hypothesize that: a) preB¿tC ¿-opioid receptor activation will depress I and GG activity while awake and to a greater extent during sleep, b) preB¿tC ¿-opioid receptor activation will not alter effluent neurochemical content and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors. Specific Aim 3 determines whether there is interdependence among neuromodulators of the HMN. We hypothesize that: a) unilateral dialysis of a ¿- opioid agonist within the HMN will decrease I and GG activity which during NREM and REM sleep will lead to SDB, b) there will be no compensatory changes in any of the measured local neurochemicals in the effluent mCSF during opioid dialysis, and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors.

描述（由申请人提供）：呼吸网络内的神经元启动并协调呼吸泵和气道肌肉激活，以调整肺通气水平（I）以维持血气稳态。化学感受器提供主要的呼吸兴奋性驱动(19,22,31,65,82)，但最终决定呼吸网络兴奋性的是兴奋性和抑制性神经调节剂的总体平衡(15,16,28,92)。内源性神经调节剂在清醒或睡眠时对 eupneic I 的贡献尚未确定，但体外证据表明“调节剂的作用是由同时进行的调节和与其他神经调节剂的相互作用决定的”(16)。我们提案的总体目标是检验神经调节相互依赖性的假设，并检验不充分的相互依赖性是否会导致睡眠呼吸障碍（SDB）和/或阿片类药物过量引起的呼吸抑制。在成年山羊中，微管将被长期植入探针的前布辛格复合体（preB¿tC）或舌下运动核（HMN）中，以便在清醒和睡眠状态下在兴奋性或抑制性神经调节剂的拮抗剂或激动剂的模拟脑脊髓液（mCSF）中进行透析。我们将测量 I、膈肌和颏舌肌 (GG) 肌肉活动以及透析 mCSF 流出液中的神经化学物质。具体目标 1 确定 preB¿tC 内多种兴奋性神经调节剂之间是否存在相互依赖性。我们假设：a) 毒蕈碱胆碱能、血清素 (5-HT2A) 或神经激肽-1 受体的拮抗剂单独对 I 和 GG 肌肉活动影响很小或没有影响，但联合使用会减弱 I 和 GG 活动，特别是在睡眠期间并导致 SDB，b) 前 B¿tC 兴奋性神经调节输入的拮抗剂将产生代偿性 拮抗剂透析部位其他神经调节剂的变化。具体目标 2 确定 preB¿tC 内兴奋性神经调节剂和 ¡-阿片受体激活的抑制性神经调节作用之间是否存在相互依赖性。我们假设：a) preB¿tC ¿-阿片受体激活会在清醒时抑制 I 和 GG 活性，并且在睡眠期间更大程度地抑制 I 和 GG 活性，b) preB¿tC ¡-阿片受体激活不会改变流出的神经化学物质含量，c) ¿-阿片受体激活诱导的 I 和 GG 活性降低将通过 ¿ 5-HT1A 或 5-HT4A 受体的激动剂和激动剂。具体目标 3 确定 HMN 的神经调节剂之间是否存在相互依赖性。我们假设：a) HMN 内的 ¿-阿片受体激动剂的单侧透析会降低 I 和 GG 活性，这在 NREM 和 REM 睡眠期间将导致 SDB，b) 在阿片类药物透析期间，排出的 mCSF 中任何测得的局部神经化学物质不会发生代偿性变化，以及 c) ¡ GG 活性将通过 ¿-阿片类激动剂和 5-HT1A 或 5-HT4A 受体激动剂的共同透析而减弱。