Endogenous cannabinoids induce fever through the activation of CB1 receptors

• Published in: British journal of pharmacology Vol. 157; no. 8; pp. 1494 - 1501
• Main Authors: Fraga, D, Zanoni, CIS, Rae, GA, Parada, CA, Souza, GEP
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2009; Nature Publishing Group
• Subjects: ACEA; AM1241; AM251; AM630; anandamide; Animals; Arachidonic Acids - pharmacology; Biological and medical sciences; Body Temperature - drug effects; Body Temperature Regulation - drug effects; Cannabinoid Receptor Modulators - physiology; Cannabinoids - pharmacology; capsazepine; Endocannabinoids; fever; Fever - etiology; Fever - metabolism; Lipopolysaccharides - pharmacology; LPS; Male; Medical sciences; Pharmacology. Drug treatments; Piperidines - pharmacology; Polyunsaturated Alkamides - pharmacology; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - physiology; Research Papers; URB597; CB1 cannabinoid receptor; ACEA; URB597; Arachidonic acid derivatives; Endogenous substance; Cannabinoid; Fever; LPS; Anandamide; AM630; Endogenous; AM1241; AM251; capsazepine; Lipopolysaccharide
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2009.00312.x

Background and purpose:  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.
Experimental approach:  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.
Key results:  Injection of anandamide [(arachidonoylethanolamide (AEA); Tocris, Ellisville, MO, USA], 0.01–1 µg i.c.v. or 0.1–100 ng intra‐hypothalamic (i.h.), induced graded increases in Tc (peaks 1.5 and 1.6°C at 4 h after 1 µg i.c.v. or 10 ng i.h.). The effect of AEA (1 µg, 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°C at 5 h after 0.1 ng) and arachidonyl‐2‐chloroethylamide (ACEA; Tocris) (selective CB1 agonist; 0.001–1 µg i.c.v.; peak 1.4°C 5 h after 0.01 µg), but (R,S)‐(+)‐(2‐Iodo‐5‐nitrobenzoyl)‐[1‐(1‐methyl‐piperidin‐2‐ylmethyl)‐1H‐indole‐3‐yl] methanone (Tocris) (selective CB2 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 CB2 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 CB1 antagonist). AM251 also reduced the fever induced by ACEA or LPS.
Conclusions and implications:  The endogenous cannabinoid AEA induces an integrated febrile response through activation of CB1 receptors. Endocannabinoids participate in the development of the febrile response to LPS constituting a target for antipyretic therapy.