Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

• Published in: The Journal of pharmacology and experimental therapeutics 2016-09, Vol.358 (3), p.492-501
• Main Authors: Kim, Seung Jae, Pilowsky, Paul M, Farnham, Melissa M J
• Format: Article
• Language: English
• Subjects: Animals; Cell Hypoxia - drug effects; Chemoreceptor Cells - cytology; Chemoreceptor Cells - drug effects; Injections, Spinal; Long-Term Potentiation - drug effects; Neuropharmacology; Orexins - administration & dosage; Orexins - pharmacology; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiology; Time Factors
• ISSN: 1521-0103; 0022-3565; 1521-0103
• DOI: 10.1124/jpet.116.234443

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; 0.1 nmol × 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 (1 nmol; 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.