title: Endogenous cannabinoids induce fever through the activation of CB1 receptors.
abstract: OBJECTIVE
  The effects of centrally administered cannabinoids on body core temperature (Tc) and the contribution of endogenous cannabinoids to thermoregulation and fever induced by lipopolysaccharide (LPS) (Sigma Chem. Co., St. Louis, MO, USA) were investigated.
  
  
  METHODS
  Drug-induced changes in Tc of male Wistar rats were recorded over 6 h using a thermistor probe (Yellow Springs Instruments 402, Dayton, OH, USA) inserted into the rectum.
  
  
  RESULTS
  Injection of anandamide [(arachidonoylethanolamide (AEA); Tocris, Ellisville, MO, USA], 0.01-1 microg i.c.v. or 0.1-100 ng intra-hypothalamic (i.h.), induced graded increases in Tc (peaks 1.5 and 1.6 degrees C at 4 h after 1 microg i.c.v. or 10 ng i.h.). The effect of AEA (1 microg, i.c.v.) was preceded by decreases in tail skin temperature and heat loss index (values at 1.5 h: vehicle 0.62, AEA 0.48). Bell-shaped curves were obtained for the increase in Tc induced by the fatty acid amide hydrolase inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (Cayman Chemical Co., Ann Arbor, MI, USA) (0.001-1 ng i.c.v.; peak 1.9 degrees C at 5 h after 0.1 ng) and arachidonyl-2-chloroethylamide (ACEA; Tocris) (selective CB(1) agonist; 0.001-1 microg i.c.v.; peak 1.4 degrees C 5 h after 0.01 microg), but (R,S)-(+)-(2-Iodo-5-nitrobenzoyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indole-3-yl] methanone (Tocris) (selective CB(2) agonist) had no effect on Tc. AEA-induced fever was unaffected by i.c.v. pretreatment with 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl) methanone (Tocris) (selective CB(2) antagonist), but reduced by i.c.v. pretreatment with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; Tocris) (selective CB(1) antagonist). AM251 also reduced the fever induced by ACEA or LPS.
  
  
  CONCLUSIONS
  The endogenous cannabinoid AEA induces an integrated febrile response through activation of CB(1) receptors. Endocannabinoids participate in the development of the febrile response to LPS constituting a target for antipyretic therapy.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Fraga
authors.forename: C I S
authors.initials: CI
authors.lastname: Zanoni
authors.forename: G A
authors.initials: GA
authors.lastname: Rae
authors.forename: C A
authors.initials: CA
authors.lastname: Parada
authors.forename: G E P
authors.initials: GE
authors.lastname: Souza
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002186:Cannabinoids / Q000494:pharmacology; D063388:Endocannabinoids; D005334:Fever / Q000209:etiology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D008070:Lipopolysaccharides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119325:arachidonyl-2-chloroethylamide; C103505:AM 251; C078814:anandamide
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