Interdependence among neuromodulators of ventilatory control

描述(申请人提供)：呼吸网络中的神经元启动和协调呼吸泵和呼吸道肌肉的激活，以调节肺通气量(I)，以维持血气平衡。化学感受器为呼吸提供主要的兴奋性驱动力(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，“调节剂的作用由与其他神经调节剂的同时调节和相互作用决定”(16)。我们建议的总体目标是测试这一神经调节相互依赖的假说，并测试不充分的相互依赖是否会导致睡眠呼吸紊乱(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Preb？tzinger复合体(Preb？ttC)或舌下运动核(HMN)，用于在清醒和睡眠状态下在模拟脑脊液(MCSF)中透析兴奋性或抑制性神经调节剂的拮抗剂或激动剂。我们将测量I、横隔膜和颧舌肌(GG)的肌肉活动，以及透析后流出的MCSF中的神经化学物质。特定目的1确定前C区内多个兴奋性神经调节剂之间是否存在相互依赖。我们假设：a)毒扁豆碱胆碱能、5-羟色胺(5-HT2a)或神经激肽-1受体的拮抗剂单独对Eupneic I和GG肌肉活动几乎没有影响，但联合使用会减弱I和GG的活动，特别是在睡眠中，并导致SDB；b)兴奋性神经调节输入到Preb的拮抗剂将在拮抗剂透析部位产生其他神经调节剂的代偿性变化。特定目的2确定兴奋性神经调节剂和阿片受体激活的抑制性神经调节效应之间是否存在相互依赖关系。我们假设：a)前阿片受体激活会在清醒时抑制I和GG的活性，在睡眠中会更大程度地抑制，b)前阿片受体的激活不会改变流出的神经化学成分，c)阿片受体激活引起的I和GG活性的降低将被阿片激动剂和5-HT1a或5-HT4A受体激动剂共透析所减弱。具体目标3确定HMN的神经调节剂之间是否存在相互依赖。我们假设：a)在HMN内单侧透析阿片激动剂将降低I和GG活性，在NREM和REM睡眠期间将导致SDB，b)在阿片透析期间流出的MCSF中的任何测量的局部神经化学物质不会有任何代偿性变化，以及c)？阿片受体激活引起的I和GG活性的降低将被？阿片激动剂和5-HT1a或5-HT4A受体激动剂共透析所减弱。

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.