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: 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
• 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

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，例如芬太尼和瑞芬太尼 (remi)，是用于治疗严重急性和慢性疼痛的高效镇痛药。在临床相关的血浆浓度下可能会发生严重的呼吸抑制（呼吸缓慢、呼吸暂停）。这些影响是否是由于对阿片类药物高度敏感的呼吸区域的抑制或分散在许多突触上造成的，目前尚未解决。寻找对阿片类药物高度敏感的靶点是设计预防阿片类药物镇痛期间呼吸抑制策略的重要一步。我们的研究表明，阿片类药物引起的呼吸缓慢并不是由 preBvtzinger 复合物 (pBC) 中 5OR 的激活引起的，pBC 是节律产生的假定基因座。初步研究表明，臂旁/Kvlliker-Fuse 核（PB-KF 区域）中脑桥呼吸群 (PRG) 神经元上/附近的 5OR 是目标。我们的工作假设是，全身 5-阿片类药物的临床浓度在 PB-KF 区域的 5OR 作用下，通过直接激活 PRG 神经元亚型上的 5OR 和/或通过其他阿片类药物的兴奋性和/或抑制性突触输入间接激活而产生呼吸缓慢。 -敏感的脑桥神经元。 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计时/切换的髓质 pBC/Bvtzinger 复合体 (BC) 神经元。此外，激活 PB-KF 区域的特定胺受体可能会逆转阿片类药物引起的呼吸抑制。为了解决这些假设，将追求以下具体目标： 目标 1：通过监测膈神经图呼吸时相持续时间的变化，定位 PB-KF 区域中通过 DAMGO（5OR 激动剂）显微注射产生阿片类药物诱导呼吸徐缓的区域（巴布亚新几内亚）。 IV remi 期间的纳洛酮（NAL；阿片类拮抗剂）显微注射将用于确定相同的 5OR 是否会产生呼吸缓慢。将使用组织化学方法来识别具有高密度 5OR 免疫反应性 (IR) 的区域，以确认功能定位区域。目标 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 抑制的影响。目标 3A：确定 PRG 神经元放电的 IV remi 抑制是否是由于 5OR 的突触后激活（由单个神经元上的 NAL 逆转皮喷射所指示）所致。 3B：对于非逆转的 PRG 神经元，通过 DAMGO 的皮喷射来确定它们是否拥有 5OR。目标4A：确定NMDA和AMPA受体介导的谷氨酸能兴奋的变化和/或GABA能和甘氨酸能抑制是否与PRG神经元的IV remi抑制有关。在 IV 呼吸缓慢之前和期间，将使用对单个 PRG 神经元的选择性拮抗剂的皮喷射。目标 5. 确定 PRG 神经元亚型上是否存在 5HT1A、D1 多巴胺和 12 肾上腺素能受体，作为对抗 5OR 诱导的抑郁症的治疗靶点。 remi 的全身静脉输注将用于在体内去大脑犬模型中产生呼吸缓慢。膈神经活动将用于测量 I 相和 E 相持续时间。多管微量移液器将用于记录单个 PRG 神经元的放电活动，同时喷射神经活性剂。 16 电极阵列探针 (NeuroNexus) 将用于在 remi 诱导的呼吸缓慢之前和期间获得多个 PRG 神经元的同时记录。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 5OR 是否介导临床浓度下全身 5-阿片类药物产生的呼吸频率抑制，将识别阿片类药物敏感的 PRG 神经元的亚型，并回答影响是否是直接和/或间接的。此外，这些研究将确定 PRG 神经元上的胺能神经调节剂受体是否提供治疗靶点，以最大限度地减少阿片类药物引起的抑郁作用。这些研究还将提供有关 PRG 神经元的功能作用以及特定神经递质/调节剂在体内各种 PRG 神经元放电模式生成中的贡献的重要新信息，以及对时相机制的新见解。