Prostaglandin E-2 differentially modulates the central control of eupnoea, sighs and gasping in mice

Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E-2 (PGE(2)) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBotzinger complex (preBotC), a medullary area that is critical for breathing. Low concentrations of PGE(2) (100-300nm) increased the sigh frequency, while higher concentrations (1-2m) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBotC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (I-Nap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (I-CAN) abolished the effect of PGE(2) on fictive eupnoea at higher concentrations. At the cellular level PGE(2) significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE(2) affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE(2) differentially modulates sigh, gasping and eupnoeic activity by differentially increasing I-Nap and I-CAN currents in preBotC neurons.