title: Activation of Medulla-Projecting Perifornical Neurons Modulates the Adrenal Sympathetic Response to Hypoglycemia: Involvement of Orexin Type 2 (OX2-R) Receptors.
abstract: Iatrogenic hypoglycemia in response to insulin treatment is commonly experienced by patients with type 1 diabetes and can be life threatening. The body releases epinephrine in an attempt to counterregulate hypoglycemia, but the neural mechanisms underlying this phenomenon remain to be elucidated. Orexin neurons in the perifornical hypothalamus (PeH) project to the rostral ventrolateral medulla (RVLM) and are likely to be involved in epinephrine secretion during hypoglycemia. In anesthetized rats, we report that hypoglycemia increases the sympathetic preganglionic discharge to the adrenal gland by activating PeH orexin neurons that project to the RVLM (PeH-RVLM). Electrophysiological characterization shows that the majority of identified PeH-RVLM neurons, including a subpopulation of orexin neurons, are activated in response to hypoglycemia or glucoprivation. Furthermore, the excitatory input from the PeH is mediated by orexin type 2 receptors in the RVLM. These results suggest that activation of orexin PeH-RVLM neurons and orexin type 2 receptors in the RVLM facilitates epinephrine release by increasing sympathetic drive to adrenal chromaffin cells during hypoglycemia.
authors.affiliation: Clinical Pharmacology and Therapeutics Unit (W.S.K., A.J.M.V.), Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria 3084, Australia; Florey Institute of Neuroscience and Mental Health (W.S.K.), University of Melbourne, Parkville, Victoria 3052, Australia; and Cardiovascular Medicine (I.J.L.-S.), Human Physiology and Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia.
authors.forename: Willian S
authors.initials: WS
authors.lastname: Korim
authors.affiliation: Clinical Pharmacology and Therapeutics Unit (W.S.K., A.J.M.V.), Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria 3084, Australia; Florey Institute of Neuroscience and Mental Health (W.S.K.), University of Melbourne, Parkville, Victoria 3052, Australia; and Cardiovascular Medicine (I.J.L.-S.), Human Physiology and Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia.
authors.forename: Ida J
authors.initials: IJ
authors.lastname: Llewellyn-Smith
authors.affiliation: Clinical Pharmacology and Therapeutics Unit (W.S.K., A.J.M.V.), Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria 3084, Australia; Florey Institute of Neuroscience and Mental Health (W.S.K.), University of Melbourne, Parkville, Victoria 3052, Australia; and Cardiovascular Medicine (I.J.L.-S.), Human Physiology and Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, South Australia 5042, Australia.
authors.forename: Anthony J M
authors.initials: AJ
authors.lastname: Verberne
mesh_terms: D000311:Adrenal Glands / Q000294:innervation / Q000378:metabolism*; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism*; D020712:Fornix, Brain; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000633:toxicity; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology; D008526:Medulla Oblongata / Q000378:metabolism*; D009287:Naphthyridines; D009434:Neural Pathways; D009474:Neurons / Q000378:metabolism*; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; C578625:Hcrtr2 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D007546:Isoquinolines; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011725:Pyridines; D014508:Urea; D004837:Epinephrine