Spinal adenosine A(2A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia

Phrenic long term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia. pLTF requires spinal serotonin receptor activation, new BDNF synthesis and TrkB receptor activation. Spinal adenosine 2A (A(2A)) receptor activation also elicits phrenic motor facilitation, but by a distinct mechanism involving new TrkB synthesis. Because extracellular adenosine increases during hypoxia, we hypothesized that A(2A) receptor activation contributes to acute intermittent hypoxia (AIH)-induced pLTF. A selective A(2A) receptor antagonist (MSX-3, 8 mu g kg-1, 12 mu l) was administered intrathecally (C4) to anaesthetized, vagotomized and ventilated male Sprague-Dawley rats before AIH (three 5 min episodes, 11% O-2). Contrary to our hypothesis, pLTF was greater in MSX-3 versus vehicle (aCSF) treated rats (97 +/- 6% vs. 49 +/- 4% at 60 min post-AIH, respectively; P < 0.05). MSX-3 and aCSF treated rats did not exhibit facilitation without AIH (time controls; 7 +/- 5% and 9 +/- 9%, respectively; P > 0.05). A second A(2A) receptor antagonist (ZM2412385, 7 mu g kg-1, 7 mu l) enhanced pLTF (85 +/- 11%, P < 0.05), but an adenosine A(1) receptor antagonist (DPCPX, 3 mu g kg-1, 10 mu l) had no effect (51% +/- 8%, P > 0.05), indicating specific A(2A) receptor effects. Intrathecal methysergide (306 mu g kg-1, 15 mu l) blocked AIH-induced pLTF in both MSX-3 and aCSF treated rats, confirming that enhanced pLTF is serotonin dependent. Intravenous MSX-3 (140 mu g kg-1, 1 ml) enhanced both phrenic (104 +/- 7% vs. 57 +/- 5%, P < 0.05) and hypoglossal LTF (46 +/- 13% vs. 28 +/- 10%; P < 0.05). In conclusion, A(2A) receptors constrain the expression of serotonin-dependent phrenic and hypoglossal LTF following AIH. A(2A) receptor antagonists (such as caffeine) may exert beneficial therapeutic effects by enhancing the capacity for AIH-induced respiratory plasticity.