Adenosine A2A Receptors Constrain Phrenic Long Term Facilitation Following Acute Intermittent Hypoxia

Phrenic Long Tem Facilitation (pLTF) is a form of serotonin‐dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires synthesis of brain derived neurotrophic factor and activation of its high affinity receptor, TrkB. Adenosine A2A receptors trans‐activate TrkB receptors in phrenic motoneurons, thereby eliciting long‐lasting phrenic facilitation (unpublished). Since hypoxia increases extracellular adenosine levels in the CNS, we hypothesized that adenosine release contributes to AIH‐induced pLTF. Thus, the A2A receptor antagonist MSX‐3 (140μg/kg, i.v.) was administered to anesthetized, ventilated, vagotomized and paralyzed male Sprague Dawley rats prior to AIH (3, 5‐min episodes, 10% O2). Contrary to our hypothesis, MSX‐3 enhanced pLTF; 60 min post‐AIH, phrenic burst amplitude was increased more in MSX‐3 (133%±7% baseline, n = 6) versus control rats (59%±8%, n = 4; p < 0.001). To localize the relevant A2A receptors, MSX‐3 was administered intrathecally at C4; enhanced pLTF was observed following intrathecal MSX‐3 (128%±11% baseline, n = 3) versus control rats (70%±13% n = 2; p< 0.05), indicating a spinal mechanism of action. Thus, A2A receptors are not necessary for pLTF, but rather constrain its expression following AIH. Although the mechanism whereby A2A receptors constrain pLTF is unknown, A2A receptor antagonists represent an interesting class of small molecules with the potential to modulate motor neuron plasticity, possibly leading to new therapeutic approaches in the treatment of respiratory insufficiency during sleep, spinal cord injury and neurodegenerative diseases (NIH HL80209 and HL07654).