PT  - JOURNAL ARTICLE
AU  - Seung Jae Kim
AU  - Paul M. Pilowsky
AU  - Melissa M. J. Farnham
TI  - Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats
AID  - 10.1124/jpet.116.234443
DP  - 2016 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 492--501
VI  - 358
IP  - 3
4099  - http://jpet.aspetjournals.org/content/358/3/492.short
4100  - http://jpet.aspetjournals.org/content/358/3/492.full
SO  - J Pharmacol Exp Ther2016 Sep 01; 358
AB  - Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n = 58). A spinally infused subthreshold dose of orexin-A (intermittent; 10 pmol × 10) produced long-term enhancement in SNA (41.4% ± 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (100 pmol; 7.3% ± 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% ± 4.5% for Almorexant at 30 mg∙kg−1 and 18.5% ± 1.2% for 75 mg∙kg−1), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.