Golder F J
Dept. of Clinical Studies-Philadelphia, School of Veterinary Medicine, Univ. of Pennsylvania, 3900 Delancey St., Philadelphia, PA 19104, USA.
J Appl Physiol (1985). 2009 Jul;107(1):217-23. doi: 10.1152/japplphysiol.00183.2009. Epub 2009 Apr 30.
Adenosine 2a (A2a) receptor agonists elicit persistent increases in phrenic nerve activity by transactivating the neurotrophin receptor, TrkB, near phrenic motoneurons. Our working model proposes that A2a receptor-mediated TrkB receptor activation strengthens glutamatergic synapses onto phrenic motoneurons. Activation of glutamate N-methyl d-aspartate (NMDA) receptors has been implicated in other models of phrenic motor plasticity. Thus we hypothesized that NMDA receptor activation also would contribute to A2a receptor-mediated phrenic motor facilitation. Adult male Sprague-Dawley rats were anesthetized with urethane, mechanically ventilated, neuromuscularly paralyzed, and bilaterally vagotomized. The A2a receptor agonist CGS-21680 and the NMDA receptor-channel blocker MK-801 were administered intrathecally over the C4 spinal segment. Phrenic nerve activity was recorded before, during, and after drug administration. MK-801 (concentration range 0.1, 1.0, 10.0, and 100 microM) was administered 30 min before CGS-21680 (50 microM). MK-801 dose-dependently blocked A2a receptor-mediated phrenic motor facilitation. When administered at 60 min post-CGS-21680, MK-801 prevented further increases in phrenic nerve activity compared with the CGS-21680 alone (CGS-21680 alone at 120 min: 114 +/- 19%; CGS-21680 and MK-801 at 60 min post-CGS-21680: 61 +/- 11%, above baseline, P < 0.05) but did not return phrenic motor output to baseline values. Our data suggest that NMDA receptor activation is necessary for de novo A2a receptor-mediated phrenic motor facilitation and that the maintenance of preexisting phrenic motor facilitation does not involve NMDA receptor-dependent mechanisms.
腺苷2a（A2a）受体激动剂通过反式激活膈运动神经元附近的神经营养因子受体TrkB，引起膈神经活动持续增加。我们的工作模型提出，A2a受体介导的TrkB受体激活增强了作用于膈运动神经元的谷氨酸能突触。谷氨酸N-甲基-D-天冬氨酸（NMDA）受体的激活在膈运动可塑性的其他模型中也有涉及。因此，我们假设NMDA受体激活也有助于A2a受体介导的膈运动易化。成年雄性Sprague-Dawley大鼠用乌拉坦麻醉，进行机械通气、神经肌肉麻痹并双侧迷走神经切断。将A2a受体激动剂CGS-21680和NMDA受体通道阻滞剂MK-801经鞘内注射到C4脊髓节段。在给药前、给药期间和给药后记录膈神经活动。在CGS-21680（50μM）给药前30分钟给予MK-801（浓度范围为0.1、1.0、10.0和100μM）。MK-801剂量依赖性地阻断A2a受体介导的膈运动易化。与单独使用CGS-21680相比，在CGS-21680给药后60分钟给予MK-801可防止膈神经活动进一步增加（单独使用CGS-21680在120分钟时：114±19%；CGS-21680和MK-801在CGS-21680给药后60分钟时：61±11%，高于基线，P<0.05），但未使膈运动输出恢复到基线值。我们的数据表明，NMDA受体激活对于新生的A2a受体介导的膈运动易化是必要的，并且维持先前存在的膈运动易化不涉及NMDA受体依赖性机制。
