Modulation of Respiratory Activity by Hypocretin-1 (Orexin A) In Situ and In Vitro

Release of hypocretins (orexins) by neurons in the lateral hypothalamus is an important contributor to arousal state, thermoregulation, feeding behavior, and has recently been proposed to play a role in breathing and central chemosensitivity. Using the in situ arterially perfused juvenile rat preparation, we determined the effect of hypocretin-1 (hcrt-1) and SB-408124 (antagonist for hypocretin receptor subtype 1, hcrt-r1) on phrenic nerve activity, a neural correlate of breathing (neuroventilation), and the neuroventilatory sensitivity to CO(2). Application of hcrt-1 through the perfusate had little effect on baseline firing. Blocking hcrt-r1, however, prevented the phrenic burst frequency response normally associated with hypercapnia. These data suggest that endogenous hypocretinergic modulation enhances neuroventilatory chemosensitivity. Further studies using the in vitro medullary slice preparation explored the effect of hcrt-1 on hypoglossal nerve activity, a correlate of ventilation in vitro. Application of exogenous hcrt-1 failed to significantly alter hypoglossal burst output in neonatal rat slices, indicating that this portion of the neuroventilatory circuit is insensitive to hcrt-1. Taken together, these data suggest that hcrt-1 is a modulator of central chemosensitivity.