Neuropharmacology of Pontine Control of Breathing Frequency
脑桥呼吸频率控制的神经药理学
基本信息
- 批准号:8962057
- 负责人:
- 金额:--
- 依托单位:
- 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 2018-09-30
- 项目状态:已结题
- 来源:
- 关键词:AcidsAcuteAddressAdverse effectsAffectAgonistAlcoholsAnalgesicsApneaAreaAxonBenzodiazepinesBrainBrain NeoplasmsBrain StemBreathingCanis familiarisCardiovascular systemCell NucleusCervical spinal cord structureCessation of lifeCharacteristicsChronicClinicalComplexDegenerative DisorderDiseaseDorsalElectrodesFentanylFlumazenilFrequenciesGenerationsGlutamatesHeadHypercapnic respiratory failureHypertensionInfusion proceduresInjuryKnowledgeLeadLifeLungMalignant NeoplasmsMeasuresMediatingMental DepressionMicroelectrodesMicroinjectionsMidazolamModelingMonitorMorphineN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuronsNeuropharmacologyNeurotransmittersNucleus solitariusObstructive Sleep ApneaOpioidOpioid AnalgesicsOxygenPainPain managementPathologicPatternPerioperativePharmaceutical PreparationsPhasePlasmaPontine structurePopulationPostoperative PainPulmonary Stretch ReceptorsReflex controlRespiratory physiologyRiskRoleSeriesSleepStimulusStructure of phrenic nerveSystemTechniquesTherapeuticTidal VolumeTraumaUnconscious StateVentilatory DepressionVeteransWorkanalogchronic painclinically relevantdesigndosagefunctional groupin vivoinsightmu opioid receptorsneurophysiologyneurotransmissionpublic health relevancereceptorremifentanilrespiratoryresponsesedativetherapeutic target
项目摘要
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):
吗啡、芬太尼和瑞芬太尼(REMI)等吗啡、芬太尼和瑞芬太尼(REMI)等吗啡类阿片受体(MOR)激动剂是治疗术后急性重度疼痛和慢性重度疼痛最有效的围手术期镇痛剂。最严重的、威胁生命的副作用限制了它们的剂量,是呼吸频率和潮气量的严重抑制(呼吸缓慢)。其他镇静剂如苯二氮类药物(BZD)和酒精的存在会增加这种风险。我们的研究表明,桥脑臂旁/K�核团(PB-KF复合体)中的神经元对与呼吸缓慢相关的低临床阿片浓度非常敏感,并有可能导致呼吸停止。我们还发现臂旁小亚区(PBSR)的神经元控制着呼吸频率(FB),似乎是介导阿片类药物诱导的呼吸迟缓的门户。局部兴奋的PBSR神经元增加了Fb,而那些降低神经元活动的神经元则降低了Fb,甚至到了呼吸暂停的程度。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作为FB的主要控制器,通过向节律性Preb�tzinger复合体(PreBC)提供兴奋性输入,产生吸气(I)和呼气(E)相神经元放电模式。全身应用阿片类药物或与镇静剂联合应用抑制PBSR神经元活动会导致严重的呼吸暂停或停搏。PBSR还通过慢适应肺伸展受体(PSR)调节I-时程(TI)和E-时程(TE)反射控制增益。为了解决上述假设,将追求以下具体目标:1)精确定位PBSR在PB-KF区附近的背侧脑桥中,根据初步发现,控制正常的FB;2)确定PBSR神经元的亚型,确定它们的轴突是否投射到BC/BC前区域,并量化它们对PSR输入的反应;3)确定各种PBSR神经元亚型的放电模式是如何产生和控制的,A)NMDA和非NMDA受体介导的谷氨酸能内源性兴奋和B)GABAA能和甘氨酸能的内源性抑制,4)确定该区域神经元上的GABAA受体是否受BZD(如咪唑安定)的调制,B)全身注射BZD是否作用于PBSR内的神经元(被微量注射的氟马西尼拮抗),以及C)微量注射BZD是否调节静脉注射瑞芬太尼的影响
其中包括:1)确定GABA受体在调节PBSR神经元以及通过微量注射选择性激动剂和拮抗剂调节TI和TE中的作用,6)确定介导AMPA刺激和高度定位电刺激在PBSR内引起的FB增加的BC前神经元亚型,以及7)表征PBSR介导的PSR反射控制对TI和TE的调制,以及B)确定这种调制是否是由于PBSR进入孤束核(NTS)改变了PSR向二级神经元的神经传递。全身静脉注射。超短效瑞芬太尼的输注将用于在活体去大脑犬模型中产生呼吸迟缓。记录膈神经活动以测量TI和TE。多管微吸管和16电极探头(NeuroNexus)将被用来同时记录PBSR神经元在微微喷射神经活性物质时的放电。对PSR输入的反应和对BC前区域的轴突投射将被用于进一步对PBSR神经元进行分类。PBSR似乎扮演着控制呼吸频率的门户的角色。因此,对这一离散区域的神经生理学和神经药理学特征的研究将为药物对呼吸频率产生不利影响的机制提供重要的见解,并提出减轻不良副作用的治疗措施。这些研究还将为PBSR神经元的功能作用和特定神经递质/调节剂对体内PBSR神经元亚型放电模式的贡献提供重要的新信息,并对呼吸机制的控制提供新的见解。
项目成果
期刊论文数量(0)
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Edward J Zuperku其他文献
Edward J Zuperku的其他文献
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{{ truncateString('Edward J Zuperku', 18)}}的其他基金
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:
8259078 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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:
8195947 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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