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J Appl Physiol 98: 1387-1395, 2005. First published November 19, 2004; doi:10.1152/japplphysiol.00914.2004
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Orexin stimulates breathing via medullary and spinal pathways

John K. Young,1 Mingfei Wu,1 Kebreten F. Manaye,1 Prabha Kc,1 Joanne S. Allard,1 Serdia O. Mack,1 and Musa A. Haxhiu1,2

1Howard University Specialized Neuroscience Research Program, Departments of Physiology and Anatomy, Washington, District of Columbia, and 2Departments of Pediatrics and Anatomy, Case Western University, Cleveland, Ohio

Submitted 20 August 2004 ; accepted in final form 10 November 2004

A central neuronal network that regulates respiration may include hypothalamic neurons that produce orexin, a peptide that influences sleep and arousal. In these experiments, we investigated 1) projections of orexin-containing neurons to the pre-Bötzinger region of the rostral ventrolateral medulla that regulates rhythmic breathing and to phrenic motoneurons that innervate the diaphragm; 2) the presence of orexin A receptors in the pre-Bötzinger region and in phrenic motoneurons; and 3) physiological effects of orexin administered into the pre-Bötzinger region and phrenic nuclei at the C3–C4 levels. We found orexin-containing fibers within the pre-Bötzinger complex. However, only 0.5% of orexin-containing neurons projected to the pre-Bötzinger region, whereas 2.9% of orexin-containing neurons innervated the phrenic nucleus. Neurons of the pre-Bötzinger region and phrenic nucleus stained for orexin receptors, and activation of orexin receptors by microperfusion of orexin in either site produced a dose-dependent, significant (P < 0.05) increase in diaphragm electromyographic activity. These data indicate that orexin regulates respiratory activity and may have a role in the pathophysiology of sleep-related respiratory disorders.

hypothalamus; pre-Bötzinger region; phrenic motor neurons; orexin-1 receptors; sleep apnea


Address for reprint requests and other correspondence: J. K. Young, Dept. of Anatomy, Howard Univ. College of Medicine, 520 W St., NW, Washington, DC 20059 (E-mail: jyoung{at}howard.edu)




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