Mu-Opioid Effects on the Central Mechanisms that Control Breathing

Mu-阿片类药物对控制呼吸的中枢机制的影响

基本信息

批准号：
8397557
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
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8397557
关键词：
AMPA Receptors Absence of pain sensation Acute Acute Pain Address Adrenergic Agents Adrenergic Receptor Adverse effects Affect Agonist Amines Analgesics Apnea Area Axon Bathing Bilateral Biogenic Amine Receptors Brain Brain Neoplasms Brain Stem Breathing Canis familiaris Cardiovascular system Cell Nucleus Cells Cervical spinal cord structure Chronic Clinical Complex Computers Consensus Degenerative Disorder Depressed mood Disease Dopamine Dopamine Agonists Dorsal Effectiveness Electrodes Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Environmental air flow Exhibits Felis catus Fentanyl Financial compensation Frequencies Generations Glutamates Glycine Receptors Head Hypertension In Vitro Infusion procedures Injury Intravenous infusion procedures Knowledge Laboratories Life Lung Malignant Neoplasms Measures Mediating Mental Depression Metabolic syndrome Methods Microinjections Modeling Monitor Morphine N-Methyl-D-Aspartate Receptors Naloxone Narcotic Antagonists Neuromodulator Neurons Neuropharmacology Neurotransmitters Norepinephrine Nucleus solitarius Obstructive Sleep Apnea Opiates Opioid Opioid Analgesics Opioid Receptor Pain Pain management Pathologic Pattern Perioperative Pharmaceutical Preparations Pharmacology Phase Plasma Pontine structure Population Postoperative Pain Property Pulmonary Stretch Receptors Pump Rattus Receptor Inhibition Respiration Respiratory physiology Role Series Serotonin Serotonin Agonists Simulate Site Structure of phrenic nerve Surface Synapses System Techniques Therapeutic Tidal Volume Time Trauma Ventilatory Depression Veterans Work adrenergic airway obstruction analog base chronic pain clinical application clinically relevant density design dosage immunoreactivity in vivo insight lateral column mu opioid receptors network models neurophysiology neurotransmission noradrenergic patient population postsynaptic presynaptic prevent receptor remifentanil research study respiratory response serotonin receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Morphine and synthetic 5-opioid receptor (5OR) analogs such as fentanyl and remifentanil (remi) are highly effective analgesics used to treat severe acute and chronic pain. Profound respiratory depression (bradypnea, apnea) can occur at clinically relevant plasma concentrations. Whether these effects are due to depression of highly opioid sensitive respiratory regions or dispersed over many synapses remains unresolved. Finding highly opioid sensitive targets is an important step in designing strategies to prevent respiratory depression during opioid analgesia. Our studies indicate that opioid-induced bradypnea does not result from activation of 5ORs in the preBvtzinger Complex (pBC), the putative locus for rhythm generation. Preliminary studies suggest that 5ORs on/near pontine respiratory group (PRG) neurons in parabrachial/ Kvlliker-Fuse nuclei (PB- KF region) are targets. Our working hypothesis is that clinical concentrations of systemic 5-opioids act at 5ORs in the PB-KF region to produce bradypnea by either direct activation of 5ORs on subtypes of PRG neurons and/or indirectly via excitatory and/or inhibitory synaptic inputs by other opioid-sensitive pontine neurons. These subtypes of PRG neurons and pulmonary stretch receptors (PSRs) inputs control the medullary pBC/Bvtzinger complex (BC) neurons responsible for respiratory phase timing/switching. Also, activation of specific amine receptors in the PB-KF region may reverse opioid-induced respiratory depression. To address these hypotheses, the following specific objectives will be pursued: Objective 1: To locate the region in the PB-KF area that produces opioid-induced bradypnea via DAMGO (5OR agonist) microinjections by monitoring changes in respiratory phase durations from the phrenic neurogram (PNG). Naloxone (NAL; opioid antagonist) microinjections during IV remi will be used to determine if the same 5ORs produce bradypnea. Histochemical methods will be used to identify regions with high densities of 5OR immunoreactivity (IR) to confirm the functionally localized regions. Objective 2: To determine which types of PRG neurons are most susceptible to IV remi and PB-KF regional DAMGO depression. Objective 3A: To determine if the IV remi depression of PRG neuronal discharge is due to postsynaptic activation of 5ORs, indicated by NAL reversal picoejected on single neurons. 3B: For nonreversed PRG neurons, to determine if they possess 5ORs via picoejection of DAMGO. Objective 4A: To determine if changes in glutamatergic excitation mediated by NMDA and AMPA receptors and/or GABAergic and glycinergic inhibition are involved in IV remi depression of PRG neurons. Picoejection of selective antagonists on single PRG neurons before and during IV remi bradypnea will be used. Objective 5. To determine if 5HT1A, D1 dopamine and 12 adrenergic receptors are present on subtypes of PRG neurons, to serve as therapeutic targets to counteract 5OR-induced depression. Systemic IV infusions of remi will be used to produce bradypnea in an in vivo decerebrate canine model. Phrenic nerve activity will be used to measure I- and E-phase duration. Multibarrel micropipettes will be used to record the discharge activity of single PRG neurons while ejecting neuroactive agents. A 16-electrode array probe (NeuroNexus) will be used to obtain simultaneous recordings of multiple PRG neurons before and during remi-induced bradypnea. Responses to antidromic activation and PSR inputs will be used to classify PRG neurons. These studies will answer whether 5ORs in the PB-KF region mediate the depression of breathing frequency produced by systemic 5-opioids at clinical concentrations, will identify subtypes of opioid sensitive PRG neurons and answer if effects are direct and/or indirect. In addition, these studies will determine whether receptors for aminergic neuromodulators on PRG neurons offer a therapeutic target to minimize opioid-induced depressant effects. These studies will also provide important new information on the functional roles of PRG neurons and the contribution of specific neurotransmitters/modulators in the generation of discharge patterns of various PRG neurons in vivo and new insights into phase-timing mechanisms.

描述（由申请人提供）：吗啡和合成5-阿片受体（5OR）类似物，例如芬太尼和雷列芬太尼（Remi）是高效的镇痛药，用于治疗严重的急性和慢性疼痛。在临床上相关的血浆浓度下，可能发生严重的呼吸抑郁症（BRADYPNEA，呼吸暂停）。这些影响是由于高度阿片类药物敏感的呼吸区域的抑郁症还是在许多突触上分散的作用尚未解决。寻找高度阿片类药物敏感靶标是设计预防阿片类镇痛过程中呼吸抑郁症的策略的重要步骤。我们的研究表明，阿片类药物诱导的dypypnea并非是由于Prebvtzinger络合物（PBC）的5OT激活，这是节奏产生的假定基因座。初步研究表明，在parabrachial/ kvlliker-Fuse-Fuse Nuclei（PB-KF区域）中，在蓬丁呼吸器组（PRG）神经元附近的5OR是目标。我们的工作假设是，PB-KF区域中5OS的全身性5-阿片类药物的临床浓度通过PRG神经元亚型上的5OR直接激活和/或通过兴奋性和/或其他阿片类敏感的pontine pontine pontine pontine pontine pontine神经元直接激活和/或间接激活PRG神经元和/或间接激活。这些PRG神经元和肺拉伸受体（PSR）的亚型输入控制髓质PBC/BVTZinger复合物（BC）神经元，负责呼吸相时机/开关。同样，PB-KF区域特异性胺受体的激活可能会逆转阿片类药物诱导的呼吸抑制。为了解决这些假设，将实现以下特定目标：目标1：在PB-KF区域定位该区域，该区域通过DAMGO（5or激动剂）显微注射产生阿片类药物诱导的BRADYPNEA，通过监测来自Phrenic Neuromk（PNG）的呼吸阶段持续时间的变化（PNG）。在静脉内remi期间，纳洛酮（NAL;阿片类拮抗剂）的显微注射将用于确定相同的5OR是否会产生脑力型。组织化学方法将用于识别高密度高5次免疫反应性（IR）的区域以确认功能局部的区域。目标2：确定哪种类型的PRG神经元最容易受到IV REMI和PB-KF区域DAMGO抑郁症的影响。目标3a：确定PRG神经元放电的IV REMI抑郁症是否是由于5OR的突触后激活引起的，这是由单个神经元上的NAL反转PICOE指示。 3B：对于非反应的PRG神经元，可以通过Damgo的picoeptosection确定它们是否具有5OR。目标4A：确定NMDA和AMPA受体介导的谷氨酸能激发的变化以及/或GABA能和糖抑制是否涉及PRG神经元的IV REMI抑郁症。在IV remi bradypnea之前和期间，将选择选择性拮抗剂对单个PRG神经元的picoeptose。目标5。确定PRG神经元亚型上是否存在5HT1A，D1多巴胺和12个肾上腺素受体，以作为抵消5or诱导的抑郁症的治疗靶标。 REMI的全身静脉输注将用于在体内杂交犬模型中产生脑型。神经活性将用于测量I-和E相持续时间。多接头微孔将用于记录单个PRG神经元的放电活性，同时驱除神经活性剂。将使用16个电极阵列探针（Neuronexus）来获得在remi诱导的BRADYPNEA之前和期间获得多个PRG神经元的同时记录。对抗体激活和PSR输入的反应将用于对PRG神经元进行分类。这些研究将回答PB-KF区域中的5OR是否介导了在临床浓度下由全身性5-阿片类药物产生的呼吸频率的抑郁症，将鉴定阿片类药物敏感的PRG神经元的亚型，并回答是否直接和/或间接作用。此外，这些研究将确定PRG神经元上氨基神经调节剂的受体是否提供了一种治疗靶标，以最大程度地减少阿片类药物诱导的抑郁作用。这些研究还将提供有关PRG神经元功能作用的重要新信息，以及特定神经递质/调节剂在体内各种PRG神经元的放电模式中的贡献，以及对相位挑选机制的新见解。