Neuropharmacology of Pontine Control of Breathing Frequency

脑桥呼吸频率控制的神经药理学

• 批准号: 9275327
• 负责人: Edward J Zuperku
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275327
• 关键词: Acids; Acute; Address; Adverse effects; Affect; Agonist; Alcohols; Analgesics; Apnea; Area; Axon; Benzodiazepines; Brain; Brain Neoplasms; Brain Stem; Breathing; Canis familiaris; Cardiovascular system; Cell Nucleus; Cervical spinal cord structure; Cessation of life; Characteristics; Chronic; Clinical; Complex; Degenerative Disorder; Disease; Dorsal; Electrodes; Fentanyl; Flumazenil; Frequencies; Generations; Glutamates; Head; Hypercapnic respiratory failure; Hypertension; Infusion procedures; Injury; Knowledge; Lead; Life; Lung; Malignant Neoplasms; Measures; Mediating; Mental Depression; Microelectrodes; Microinjections; Midazolam; Modeling; Monitor; Morphine; N-Methylaspartate; Neurons; Neuropharmacology; Neurotransmitters; Nucleus solitarius; Obstructive Sleep Apnea; Opioid; Oxygen; Pain; Pain management; Pathologic; Pattern; Perioperative; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Pontine structure; Population; Postoperative Pain; Pulmonary Stretch Receptors; Reflex control; Respiratory physiology; Risk; Role; Series; Sleep; Stimulus; Structure of phrenic nerve; System; Techniques; Therapeutic; Tidal Volume; Trauma; Unconscious State; Ventilatory Depression; Veterans; analog; chronic pain; clinically relevant; design; dosage; functional group; in vivo; insight; mu opioid receptors; neurophysiology; neurotransmission; public health relevance; receptor; remifentanil; respiratory; response; sedative; therapeutic target

DESCRIPTION (provided by applicant): Mu-opioid receptor (MOR) agonists such as morphine, fentanyl and remifentanil (remi) are the most effective perioperative analgesics for both acute severe postoperative pain and chronic severe pain states. The most serious, life-threatening side effect, which limits their dosage, is profound depression of breathing rate (bradypnea) and tidal volume. This risk is increased in the presence of other sedatives such as benzodiazepines (BZDs) and alcohol. Our studies indicate that neurons in the parabrachial/ K�lliker-Fuse nuclei (PB-KF complex) of the pons are very sensitive to low clinical opioid concentrations associated with bradypnea and have the potential to cause respiratory arrest. We have also discovered that neurons in a small parabrachial subregion (PBSR) control breathing frequency (fB) and appear to be the portal that mediates the opioid-induced bradypnea. Localized excitation of PBSR neurons increase fB, while those that decrease neuronal activity decrease fB even to the point of apnea. Thus, any drugs that affect the activity of PBSR neurons will have a major impact on breathing. Our working hypothesis is the PBSR functions as the major controller of fB by providing excitatory inputs to the rhythmogenic preB�tzinger Complex (preBC) that produces phasic inspiratory (I) and expiratory (E) neuronal discharge patterns. Depression of PBSR neuronal activity by systemically administered opioids alone or combined with sedatives leads to severe bradypnea or arrest. The PBSR also modulates the gain of the reflex control of I-duration (TI) and E-duration (TE) mediated by slowly adapting pulmonary stretch receptors (PSRs). To address the above hypotheses, the following specific aims will be pursued: 1) Precisely locate the PBSR in the dorsal pons near the PB-KF area that controls eupneic fB as suggested by preliminary findings, 2) Identify the PBSR neuron subtypes, determine if their axons project to the preBC/BC region and quantify their responses to PSR inputs, 3) determine how the discharge patterns of the various PBSR neuron subtypes are generated and controlled by A) NMDA and nonNMDA receptor mediated glutamatergic endogenous excitation and B) by GABAergic and glycinergic endogenous inhibition, 4) determine A) whether the GABAA receptors on neurons within this region are modulated by BZDs (e.g., midazolam), B) whether systemically-administered BZDs act on neurons within the PBSR (antagonized by microinjected flumazenil), and C) whether microinjected BZDs modulate the effects of iv remifentanil-induced bradypnea, 5) determine the role of GABAB receptors in the modulation of PBSR neurons and of TI and TE via microinjections of selective agonists and antagonists, 6) identify preBC neuron subtypes that mediate increases in fB evoked within the PBSR by AMPA stimulation and highly localized electrical stimuli, and 7 A) characterize the modulation of the PSR reflex control of TI and TE mediated by the PBSR, and B) and determine whether this modulation is due to PBSR inputs to the nucleus of the solitary tract (NTS) that alter the PSR neurotransmission to the second order neurons. Systemic i.v. infusions of ultra short-acting remifentanil will be used to produce bradypnea in an in vivo decerebrate canine model. Phrenic nerve activity will be recorded to measure TI and TE. Multibarrel micropipettes and a 16-electrode probe (NeuroNexus) will be used to simultaneously record the discharge of PBSR neurons while picoejecting neuroactive agents. Responses to PSR inputs and axon projections to the preBC region will be used to further classify the PBSR neurons. The PBSR appears to act as the portal through which breathing rate is controlled. Thus, the study of the neurophysiological and neuropharmacological characteristics of this discrete region will provide major insight into the mechanisms by which drugs adversely affect breathing frequency and suggest therapeutic measures to alleviate undesirable side effects. These studies will also provide important new information on the functional roles of PBSR neurons and the contribution of specific neurotransmitters/modulators to the discharge patterns of PBSR neuron subtypes in vivo and new insights into control of breathing mechanisms.

描述（由申请人提供）： Mu-阿片受体 (MOR) 激动剂，如吗啡、芬太尼和瑞芬太尼 (remi)，是治疗急性严重术后疼痛和慢性严重疼痛状态最有效的围手术期镇痛药。最严重、危及生命的副作用是呼吸频率（呼吸缓慢）和潮气量的严重抑制，这限制了其剂量。如果存在苯二氮卓类 (BZD) 和酒精等其他镇静剂，这种风险会增加。我们的研究表明，脑桥臂旁/Külliker-Fuse 核（PB-KF 复合体）中的神经元对与呼吸缓慢相关的低临床阿片类药物浓度非常敏感，并且有可能导致呼吸骤停。我们还发现，臂旁小分区 (PBSR) 中的神经元控制呼吸频率 (fB)，并且似乎是介导阿片类药物引起的呼吸缓慢的门户。 PBSR 神经元的局部兴奋会增加 fB，而那些减少神经元活动的神经元则会降低 fB，甚至导致呼吸暂停。因此，任何影响 PBSR 神经元活动的药物都会对呼吸产生重大影响。我们的工作假设是 PBSR 通过向节律性前 Bützinger 复合体 (preBC) 提供兴奋性输入来充当 fB 的主要控制器，从而产生阶段性吸气 (I) 和呼气 (E) 神经元放电模式。单独全身施用阿片类药物或与镇静剂联合使用，可抑制 PBSR 神经元活动，导致严重的呼吸缓慢或呼吸骤停。 PBSR 还调节由缓慢适应肺牵张受体 (PSR) 介导的 I 持续时间 (TI) 和 E 持续时间 (TE) 反射控制的增益。为了解决上述假设，将追求以下具体目标：1）根据初步发现，精确定位控制 eupneic fB 的 PB-KF 区域附近的背侧脑桥中的 PBSR，2）识别 PBSR 神经元亚型，确定它们的轴突是否投射到 preBC/BC 区域并量化它们对 PSR 输入的反应，3）确定 PBSR 神经元的放电模式如何 各种 PBSR 神经元亚型由 A) NMDA 和非 NMDA 受体介导的谷氨酸内源性兴奋和 B) 通过 GABA 能和甘氨酸内源性抑制产生和控制，4) 确定 A) 该区域内神经元上的 GABAA 受体是否受 BZD（例如咪达唑仑）调节，B) 是否全身给药 BZD 作用于 PBSR 内的神经元（被微注射氟马西尼拮抗），C) 微注射 BZD 是否调节静脉注射瑞芬太尼诱导的作用 呼吸缓慢，5) 通过显微注射选择性激动剂和拮抗剂确定 GABAB 受体在 PBSR 神经元以及 TI 和 TE 调节中的作用，6) 识别介导 AMPA 刺激和高度局部电刺激在 PBSR 内诱发的 fB 增加的前 BC 神经元亚型，7A) 表征 TI 和 TE 的 PSR 反射控制的调节 B) 介导，并确定这种调节是否是由于 PBSR 输入到孤束核 (NTS)，从而改变了到二级神经元的 PSR 神经传递。全身静脉注射超短效瑞芬太尼输注将用于在体内去大脑犬模型中产生呼吸缓慢。将记录膈神经活动以测量 TI 和 TE。多管微量移液器和 16 电极探针 (NeuroNexus) 将用于在皮喷射神经活性剂的同时记录 PBSR 神经元的放电。对 PSR 输入的响应和对 preBC 区域的轴突投影将用于进一步对 PBSR 神经元进行分类。 PBSR 似乎充当控制呼吸频率的门户。因此，对这个离散区域的神经生理学和神经药理学特征的研究将深入了解药物对呼吸频率产生不利影响的机制，并提出减轻不良副作用的治疗措施。这些研究还将提供关于 PBSR 神经元的功能作用以及特定神经递质/调节剂对 PBSR 神经元亚型体内放电模式的贡献的重要新信息，以及对呼吸机制控制的新见解。