The hypocretins/orexins (Hcrts/ORXs) act within brain to stimulate autonomic function and have been demonstrated to be physiologic regulators of arousal state. Neuroendocrine and metabolic effects of these peptides, some related to sleep/wakefulness and arousal state, are just now being discovered. Indeed, these peptides exert a combination of autonomic (sympathoexcitation), behavioral (arousal), and neuroendocrine (ACTH release) effects in brain that suggests important roles for them in the CNS response to stress. However, little is known of the exact sites of action of these peptides in brain, or their mechanisms of action. We have identified neurons in hypothalamus and brain stem cardiovascular centers that are excited by orexin, suggesting a cellular basis for our reported actions of the peptide on autonomic function and stress hormone (ACTH) release (vide infra). We also have identified a pituitary action of the peptides to affect CRH-induced ACTH release. We seek to elucidate: 1) the cellular events and signal transduction pathways underlying the pituitary actions of Hcrt/ORX on ACTH release, 2) the integrated autonomic (neuroendocrine and cardiovascular) actions, underlying cellular mechanisms, and specific neuronal circuitry through which Hcrt/ORX exerts physiological actions in the hypothalamic paraventricular nucleus (PVN), 3) the integrated cardiovascular actions, underlying cellular mechanisms, and specific neuronal circuitry, through which Hcrt/ORX exerts physiological actions in the nucleus tractus solitarius (NTS), and 4) the membrane properties of Hcrt/ORX producing neurons in the lateral hypothalamic/perifornical area (LH/PFA), extrinsic factors controlling their excitability, and functional connectivity with critical autonomic nuclei in other regions of the brain. We propose to identify the exact sites of action of these peptides, provide insight into the receptor specificity of their pharmacologic effects and establish model systems for the study of the physiologic relevance of the interactions of the Hcrts/ORXs with brain and pituitary systems activated during stress. Long-term goals are to identify the physiologic relevance of these peptides in the central control of autonomic function and in the neuroendocrine regulation of anterior pituitary function, and to relate those functions to the cardiovascular responses to, and consequences of, stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068652-04
Application #
6938576
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Lathrop, David A
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$412,468
Indirect Cost
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Samson, Willis K (2009) The evolving story of orexin biology: the hits keep coming. F1000 Biol Rep 1:85
Samson, Willis K; Zhang, Jian V; Avsian-Kretchmer, Orna et al. (2008) Neuronostatin encoded by the somatostatin gene regulates neuronal, cardiovascular, and metabolic functions. J Biol Chem 283:31949-59
Samson, Willis K; Bagley, Sara L; Ferguson, Alastair V et al. (2007) Hypocretin/orexin type 1 receptor in brain: role in cardiovascular control and the neuroendocrine response to immobilization stress. Am J Physiol Regul Integr Comp Physiol 292:R382-7
Smith, P M; Samson, W K; Ferguson, A V (2007) Cardiovascular actions of orexin-A in the rat subfornical organ. J Neuroendocrinol 19:7-13
Taylor, Meghan M; Bagley, Sara L; Samson, Willis K (2006) Intermedin/Adrenomedullin-2 inhibits growth hormone release from cultured, primary anterior pituitary cells. Endocrinology 147:859-64