Abstract
Intermittent spinal serotonin receptor activation elicits phrenic motor facilitation (pMF), a form of spinal respiratory motor plasticity. Episodic activation of either serotonin type 2 (5-HT(2)) or type 7 (5-HT(7)) receptors elicits pMF, although they do so via distinct cellular mechanisms known as the Q (5-HT(2)) and S (5-HT(7)) pathways to pMF. When coactivated, these pathways interact via mutual cross-talk inhibition. Although we have a rudimentary understanding of mechanisms mediating cross-talk interactions between spinal 5-HT(2) subtype A (5-HT(2A)) and 5-HT(7) receptor activation, we do not know if similar interactions exist between 5-HT(2) subtype B (5-HT(2B)) and 5-HT(7) receptors. We confirmed that either spinal 5-HT(2B) or 5-HT(7) receptor activation alone elicits pMF and tested the hypotheses that 1) concurrent activation of both receptors suppresses pMF due to cross-talk inhibition; 2) 5-HT(7) receptor inhibition of 5-HT(2B) receptor-induced pMF requires protein kinase A (PKA) activity; and 3) 5-HT(2B) receptor inhibition of 5-HT(7) receptor-induced pMF requires NADPH oxidase (NOX) activity. Selective 5-HT(2B) and 5-HT(7) receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) to anesthetized, paralyzed, and ventilated rats. Whereas integrated phrenic nerve burst amplitude increased after selective spinal 5-HT(2B) or 5-HT(7) receptor activation alone (i.e., pMF), pMF was no longer observed with concurrent 5-HT(2B) and 5-HT(7) receptor agonist administration. With concurrent receptor activation, pMF was rescued by inhibiting either NOX or PKA activity, demonstrating their roles in cross-talk inhibition between these pathways to pMF. This report demonstrates cross-talk inhibition between 5-HT(2B)- and 5-HT(7) receptor-induced pMF and that NOX and PKA activity are necessary for that cross-talk inhibition.