NMDA receptor activation is necessary for A2a‐induced phrenic motor facilitation

Abstract

Adenosine 2a receptor agonists elicit persistent increases in phrenic motor output by transactivating the TrkB receptor near phrenic motoneurons. Our working model proposes that A2a‐induced TrkB activation strengthens glutamatergic synapses onto phrenic motoneurons. Activation of the glutamate NMDA receptors have been implicated in other forms of phrenic motor plasticity. Thus, we hypothesized that NMDA receptor activation also is necessary for A2a‐induced phrenic motor facilitation. Adult male Sprague Dawley rats were anesthetized with urethane, mechanically ventilated, neuromuscularly paralyzed, and bilaterally vagotomized. An catheter was positioned with the tip overlying the C4 spinal segment for intrathecal drug administration. Phrenic motor output was recorded before, during, and after intrathecal drug administration. Baseline phrenic motor output was established at 3 mmHg above an individual's apneic threshold. MK801, an NMDA receptor antagonist, was injected intrathecally (dose range 0.1, 1.0, 10.0, and 100 μM) 30 min before intrathecal administration of the A2a receptor agonist CGS 21680 (50 μM). MK801 dose‐dependently blocked A2a‐induced phrenic motor facilitation. The dose‐response curve was classically sigmoidal with an IC50 of 0.8 μM for MK801. These data demonstrate that NMDA receptor activation is necessary for A2a‐induced phrenic motor facilitation.