title: Spinal NMDA receptor activation is necessary for de novo, but not the maintenance of, A2a receptor-mediated phrenic motor facilitation.
abstract: 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.
authors.affiliation: Dept. of Clinical Studies-Philadelphia, School of Veterinary Medicine, Univ. of Pennsylvania, 3900 Delancey St., Philadelphia, PA 19104, USA. golderf@vet.upenn.edu
authors.forename: F J
authors.initials: FJ
authors.lastname: Golder
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000959:Antihypertensive Agents; D018696:Neuroprotective Agents; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D016291:Dizocilpine Maleate; D020813:Receptor, trkB; D000241:Adenosine