Endogenous cannabinoids induce fever through the activation of CB1 receptors.
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.
Fraga
D
D
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Zanoni
C I S
CI
Rae
G A
GA
Parada
C A
CA
Souza
G E P
GE
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
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
Science. 1969 Mar 28;163(3874):1464-7
5773112
Brain Res. 1991 Oct 25;562(2):199-206
1773338
Braz J Med Biol Res. 2001 Mar;34(3):301-14
11262580
Peptides. 2000 Nov;21(11):1735-42
11090929
Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:619-31
12432948
Handb Exp Pharmacol. 2005;(168):1-51
16596770
Biochem Pharmacol. 1995 Jun 29;50(1):83-90
7605349
J Pharmacol Exp Ther. 2007 Mar;320(3):1127-33
17194800
Pharmacol Biochem Behav. 1993 Dec;46(4):967-72
7906042
Br J Pharmacol. 1982 Feb;75(2):409-14
6313110
Curr Med Chem. 2004 Dec;11(24):3185-202
15579007
J Appl Physiol (1985). 2002 Jun;92(6):2667-79
12015388
Neuropharmacology. 1995 Feb;34(2):175-80
7617143
J Am Chem Soc. 1965 Jul 20;87:3273-5
14324315
Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):243-56
12052040
Res Commun Chem Pathol Pharmacol. 1972 Sep;4(2):281-8
5074527
J Neuroendocrinol. 2008 May;20 Suppl 1:10-4
18426493
Neuroscience. 1998 Mar;83(2):393-411
9460749
J Exp Med. 1986 Jun 1;163(6):1433-50
3486936
Biochem Pharmacol. 1999 Feb 15;57(4):417-23
9933030
Pharmacol Ther. 1997;74(2):129-80
9336020
Science. 1997 Aug 22;277(5329):1094-7
9262477
J Pharmacol Exp Ther. 2002 Jun;301(3):963-8
12023525
Eur J Immunol. 1988 Jun;18(6):957-9
3260188
Tetrahedron. 1965 May;21(5):1223-9
5879350
Behav Pharmacol. 1999 May;10(3):327-31
10780247
J Neurochem. 1997 Aug;69(2):631-8
9231721
Nature. 1996 Nov 7;384(6604):83-7
8900284
Br J Pharmacol. 1977 May;60(1):65-71
884391
Crit Rev Neurobiol. 1999;13(3):243-81
10803637
Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R411-20
18032464
Addict Biol. 2008 Jun;13(2):147-59
18482430
Br J Pharmacol. 1998 Oct;125(3):542-8
9806338
Eur J Pharmacol. 1977 Nov 15;46(2):93-9
590330
Nature. 1993 Sep 2;365(6441):61-5
7689702
Rev Infect Dis. 1984 Jan-Feb;6(1):51-95
6369481
Science. 1992 Dec 18;258(5090):1946-9
1470919
Experientia. 1971 Oct 15;27(10):1191-2
5127877
Clin Infect Dis. 2000 Oct;31 Suppl 5:S157-61
11113018
J Lipid Res. 1997 Dec;38(12):2383-98
9458263
J Neurosci Methods. 1985 Apr;13(2):139-43
3889509
Physiol Behav. 1990 May;47(5):963-91
2201986
Biochim Biophys Acta. 1999 Oct 18;1441(1):77-84
10526230
Nature. 1990 Aug 9;346(6284):561-4
2165569
Horm Metab Res. 1990 Dec;22(12):616-8
2076859