title: Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors.
abstract: Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Jesse Lea
authors.initials: JL
authors.lastname: Carlin
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Piñol
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.).
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch (J.L.C., C.X., R.A.P., M.L.R.), Molecular Recognition Section, Laboratory of Bioorganic Chemistry (D.K.T., K.A.J.), and Mouse Metabolism Core (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (Z.C., D.S.) marc.reitman@nih.gov.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*
chemical_list: D058909:Adenosine A3 Receptor Agonists; D043684:Receptor, Adenosine A3; D011969:Receptors, Histamine H1