title: Neurological basis of AMP-dependent thermoregulation and its relevance to central and peripheral hyperthermia.
abstract: Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5'-monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5'-nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5'-nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5'-monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5'-nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Muzzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.forename: Alessio
authors.initials: A
authors.lastname: Masi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Coppi
authors.forename: Chiara
authors.initials: C
authors.lastname: Traini
authors.forename: Roberta
authors.initials: R
authors.lastname: Felici
authors.forename: Maria
authors.initials: M
authors.lastname: Pittelli
authors.forename: Leonardo
authors.initials: L
authors.lastname: Cavone
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.forename: Flavio
authors.initials: F
authors.lastname: Moroni
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism* / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001833:Body Temperature Regulation; D015232:Dinoprostone / Q000009:adverse effects / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000009:adverse effects / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010120:Oxytocics / Q000009:adverse effects / Q000494:pharmacology; D011301:Preoptic Area / Q000378:metabolism* / Q000473:pathology; D063487:Prescription Drug Misuse; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D009419:Nerve Tissue Proteins; D010120:Oxytocics; D043682:Receptor, Adenosine A1; D000249:Adenosine Monophosphate; D015720:5'-Nucleotidase; D015232:Dinoprostone; D018817:N-Methyl-3,4-methylenedioxyamphetamine