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

• 批准号: 7925889
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925889
• 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

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. PUBLIC HEALTH RELEVANCE: The vital importance of adequate respiratory function in the face of the polymorbidity of our veterans cannot be overemphasized. Many pathologic conditions that are common to the veteran population compromise respiratory function and include: diseases of the airways, lungs, and cardiovascular system, injuries to the head, brain, and cervical spinal cord, brain tumors, central and obstructive sleep apneas associated with the metabolic syndrome and hypertension. In addition, this patient population has a frequent need for potent opioid analgesics, be it for perioperative pain control or chronic pain from trauma, degenerative diseases or cancer. The proposed studies will contibute to the detailed knowledge and understanding of the control of breathing and of the neurophysiology and neuropharmacology of various respiratory neuron groups. This type of information is a necessary prerequisite for designing specific medications and therapeutic strategies that allow adequate pain control by opioids while minimizing respiratory depression.

描述（由申请人提供）： 吗啡和合成的5-阿片受体（5 OR）类似物，如芬太尼和雷米芬太尼（remi）是用于治疗严重急性和慢性疼痛的高效镇痛药。在临床相关血浆浓度下可能发生严重呼吸抑制（呼吸过缓、呼吸暂停）。这些效应是否是由于高度阿片敏感的呼吸区域的抑制或分散在许多突触上仍然没有解决。寻找高度阿片敏感的靶点是设计策略以防止阿片镇痛期间呼吸抑制的重要一步。我们的研究表明，阿片类药物诱导的呼吸徐缓不是由前Bvtzinger复合体（pBC）中的5 OR激活引起的，pBC是产生节律的假定位点。初步研究表明，脑桥呼吸组（PRG）神经元上/附近的臂旁核/Kvliker-KF核（PB-KF区）的5 OR是靶点。我们的工作假设是，全身性5-阿片类药物的临床浓度作用于PB-KF区域的5 OR，通过直接激活PRG神经元亚型上的5 OR和/或间接通过其他阿片类药物敏感的脑桥神经元的兴奋性和/或抑制性突触输入来产生呼吸缓慢。PRG神经元和肺牵张受体（PSR）输入的这些亚型控制负责呼吸相位定时/切换的延髓pBC/Bvtzinger复合体（BC）神经元。此外，PB-KF区域中特异性胺受体的激活可能逆转阿片类药物诱导的呼吸抑制。为了解决这些假设，将追求以下具体目标：目标1：通过监测膈神经图（PNG）的呼吸相持续时间变化，定位PB-KF区域中通过DAMGO（5 OR激动剂）微量注射产生阿片类药物诱导的呼吸缓慢的区域。在IV remi期间，将使用纳洛酮（NAL;阿片类拮抗剂）微量注射来确定相同的5 OR是否会产生呼吸徐缓。将使用组织化学方法鉴定具有高密度5 OR免疫反应性（IR）的区域，以确认功能定位区域。目的2：确定哪些类型的PRG神经元最容易受到IV remi和PB-KF区域DAMGO抑制。目标3A：为了确定PRG神经元放电的IV remi抑制是否是由于5 OR的突触后激活，由单个神经元上的NAL逆转picoemitted指示。3B：对于非逆转的PRG神经元，以确定它们是否具有通过DAMGO的皮可喷射的5 OR。目标4A：确定由NMDA和AMPA受体介导的多巴胺能兴奋和/或GABA能和甘氨酸能抑制的变化是否参与PRG神经元的IV remi抑制。在IV remi呼吸缓慢之前和期间，将使用单个PRG神经元上的选择性拮抗剂的皮可喷射。目标5.确定PRG神经元亚型上是否存在5 HT 1A、D1多巴胺和12肾上腺素能受体，以作为对抗5 OR诱导的抑郁症的治疗靶点。在体内去大脑犬模型中，将使用雷米的全身IV输注来产生呼吸徐缓。膈神经活动将用于测量I期和E期持续时间。多管微量移液器将用于记录单个PRG神经元在喷射神经活性剂时的放电活动。将使用16电极阵列探针（NeuroNexus）在雷米诱发呼吸徐缓之前和期间同时记录多个PRG神经元。对逆向激活和PSR输入的响应将用于对PRG神经元进行分类。这些研究将回答PB-KF区域中的5 OR是否介导临床浓度下全身性5-阿片类药物产生的呼吸频率抑制，将鉴定阿片类药物敏感PRG神经元的亚型，并回答影响是直接和/或间接的。此外，这些研究将确定PRG神经元上的胺能神经调质受体是否提供了一个治疗靶点，以最大限度地减少阿片类药物诱导的阿片类药物的作用。这些研究还将提供重要的新信息PRG神经元的功能作用和特定的神经递质/调制器在体内产生的各种PRG神经元的放电模式和相位定时机制的新见解的贡献。 公共卫生相关性： 面对退伍军人的多发病率，充分的呼吸功能的至关重要性怎么强调都不过分。退伍军人群体常见的许多病理状况损害呼吸功能，包括：气道、肺和心血管系统疾病，头部、大脑和颈脊髓损伤，脑肿瘤，与代谢综合征和高血压相关的中枢性和阻塞性睡眠呼吸暂停。此外，该患者人群经常需要强效阿片类镇痛药，用于围手术期疼痛控制或创伤、退行性疾病或癌症引起的慢性疼痛。所提出的研究将有助于对呼吸控制以及各种呼吸神经元群的神经生理学和神经药理学的详细了解和理解。这类信息是设计特定药物和治疗策略的必要前提，这些药物和治疗策略允许阿片类药物充分控制疼痛，同时最大限度地减少呼吸抑制。