ROLE OF EXCITATORY AMINO-ACIDS IN THE GENERATION AND TRANSMISSION OF RESPIRATORY DRIVE IN NEONATAL RAT
ROLE OF EXCITATORY AMINO-ACIDS IN THE GENERATION AND TRANSMISSION OF RESPIRATORY DRIVE IN NEONATAL RAT
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DOI：
10.1113/jphysiol.1991.sp018622
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发表时间：
1991-06-01
影响因子：
5.5
通讯作者：
FELDMAN, JL
中科院分区：
文献类型：
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作者：
GREER, JJ;SMITH, JC;FELDMAN, JL
1. 在离体新生大鼠脑干-脊髓标本上研究了兴奋性氨基酸参与节律性呼吸驱动的产生和传递。 研究的兴奋性氨基酸受体的亚类包括：（i）N-甲基-D-天冬氨酸（NMDA）受体，（ii）（R，S）-α-氨基-3-羟基-5-甲基异恶唑-4-丙酸氢溴酸盐（AMPA）和红藻氨酸（非NMDA）受体和（iii）2-氨基-4-膦酰基丁酸（AP-4）敏感性受体。 呼吸运动神经元群放电记录从舌咽（IX），迷走（X），和舌下（XII）颅神经，以及颈（C1-C5）和胸（T2-T5）脊髓腹根。 这种活动产生于运动神经元池，运动神经元池将呼吸驱动传递到上呼吸道、附件、隔膜和肋间肌。 运动神经放电的扰动进行了分析后，兴奋性氨基酸受体拮抗剂或激动剂被添加到周围的脊髓或脑干的沐浴解决方案。 兴奋性氨基酸受体拮抗剂包括：（i）NMDA受体拮抗剂（+）-5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚氨基-H-马来酸盐（MK-801）和（ii）非NMDA受体拮抗剂6-氰基-7-硝基喹喔啉-2，3-二酮（CNQX）。 激动剂包括：（i）NMDA，（ii）非NMDA受体激动剂AMPA和红藻氨酸。 研究了AP-4对AP-4敏感受体的干扰作用和二氢红藻氨酸（DHK）对兴奋性氨基酸摄取的抑制作用. 通过CNQX阻断延髓中的非NMDA受体导致呼吸运动神经元爆发频率的拮抗剂浓度依赖性降低。 用红藻氨酸或AMPA激活非NMDA受体引起爆发频率的浓度依赖性增加，与CNQX竞争性相互作用。 用DHK抑制延髓兴奋性氨基酸摄取导致呼吸频率可逆性、剂量依赖性增加。 当用MK-801阻断延髓NMDA受体时，DHK诱导了类似的呼吸频率增加，证实了内源性释放的兴奋性氨基酸作用于非NMDA受体以调节节律。 非NMDA受体阻滞剂分别作用于延髓和脊髓时，降低并最终消除了颅侧和脊髓呼吸运动神经元的综合放电幅度. 用MK-801阻断延髓中的NMDA受体不会干扰自发呼吸爆发频率，尽管NMDA浴应用产生了频率的剂量依赖性增加，与MK-801存在非竞争性相互作用。 MK-801也没有扰乱的幅度颅或球脊髓前运动神经元放电。 脊髓内NMDA受体的阻断引起吸气运动神经元放电幅度相对较小（10-30%）的降低。 AP-4应用于延髓浴液不影响呼吸节律，颅运动神经元的振幅，或球脊髓前运动神经元放电。 相反，在脊髓水平，AP-4有效地抑制并最终阻断膈和肋间运动神经元的吸气放电，而它仅引起C1-C2吸气放电幅度的小幅降低。 我们的结论是，呼吸节律的产生在体外新生大鼠脑干脊髓是依赖于和调制内源性释放的兴奋性氨基酸作用于非NMDA受体。 吸气驱动向颅、副、膈和肋间运动神经元池的传递也依赖于非NMDA受体的激活。 NMDA受体的激活对脑干和脊髓运动神经元池的吸气驱动传递贡献相对较小的组分，并且对于节律发生不是必需的。 AP-4敏感受体在吸气驱动传递到膈和肋间运动神经元池中起重要作用，但不参与节律发生或驱动传递到颅和附属运动神经元。 这表明在脊髓和颅突触通路中介导吸气驱动传递的受体机制的功能异质性。
1. The involvement of excitatory amino acids in the generation and transmission of rhythmic respiratory drive was studied in an in vitro neonatal rat brain stem-spinal cord preparation. The subclasses of excitatory amino acid receptors studied included: (i) N-methyl-D-aspartate (NMDA) receptors, (ii) (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) and kainate (non-NMDA) receptors and (iii) 2-amino-4-phosphonobutyric acid (AP-4)-sensitive receptors. Respiratory motoneurone population discharge was recorded from glossopharyngeal (IX), vagus (X), and hypoglossal (XII) cranial nerves, as well as cervical (C1-C5) and thoracic (T2-T5) spinal ventral roots. This activity is generated in the motoneurone pools that transmit respiratory drive to upper airway, accessory, diaphragm and intercostal muscles. Perturbations of motor nerve discharge were analysed after excitatory amino acid receptor antagonists or agonists were added to bathing solutions surrounding either the spinal cord or brain stem. The excitatory amino acid receptor antagonists include: (i) NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imin-H-maleate (MK-801) and (ii) non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The agonists included: (i) NMDA, (ii) non-NMDA receptor agonists AMPA and kainic acid. The effects of perturbations of AP-4-sensitive receptors with AP-4, and of inhibiting excitatory amino acid uptake with dihydrokainic acid (DHK) were also studied.2. Block of non-NMDA receptors in the medulla by CNQX resulted in an antagonist concentration-dependent decrease in the respiratory motoneuronal burst frequency. Non-NMDA receptor activation with kainic acid or AMPA caused a concentration-dependent increase in burst frequency, with competitive interactions with CNQX.3. Inhibition of excitatory amino acid uptake in the medulla with DHK resulted in a reversible, dose-dependent increase in respiratory frequency. A similar increase in respiratory frequency was induced by DHK when medullary NMDA receptors were blocked with MK-801, confirming that endogenously released excitatory amino acids act at non-NMDA receptors to modulate rhythm.4. Non-NMDA receptor block reduced and ultimately abolished the amplitude of integrated cranial and spinal respiratory motoneuronal discharge when added to the solution bathing the medulla and spinal cord, respectively.5. NMDA receptor block in the medulla with MK-801 did not perturb the spontaneous respiratory burst frequency, although bath application of NMDA produced a dose-dependent increase in frequency, with non-competitive interactions with MK-801. MK-801 also did not perturb the amplitude of cranial or bulbospinal premotoneurone discharge. Block of NMDA receptors within the spinal cord caused a relatively small (10-30%) decrease in the amplitude of inspiratory motoneurone discharge.6. AP-4 applied to the medullary bathing solution did not affect respiratory rhythm, the amplitude of cranial motoneurone, or bulbospinal premotoneurone discharge. In contrast, at the spinal cord level, AP-4 potently inhibited and ultimately blocked inspiratory discharge of phrenic and intercostal motoneurones while it caused only a small reduction in the amplitude of C1-C2 inspiratory discharge.7. We conclude that respiratory rhythm generation in the in vitro neonatal rat brain stem-spinal cord is dependent on and modulated by endogenously released excitatory amino acids acting at non-NMDA receptors. The transmission of inspiratory drive to cranial, accessory, phrenic and intercostal motoneurone pools also depends upon activation of non-NMDA receptors. Activation of NMDA receptors contributes a relatively small component of inspiratory drive transmission to brain stem and spinal motoneurone pools, and is not necessary for rhythmogenesis. AP-4-sensitive receptors are importantly involved in inspiratory drive transmission to phrenic and intercostal motoneurone pools, but not in rhythmogenesis or drive transmission to cranial and accessory motoneurones. This indicates a functional heterogeneity of receptor mechanisms mediating transmission of inspiratory drive in spinal and cranial synaptic pathways.