title: The hypothermic response to bacterial lipopolysaccharide critically depends on brain CB1, but not CB2 or TRPV1, receptors.
abstract: Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide(AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22◦C, a moderate dose of LPS (25 - 100 μg kg−1 I.V.) induced a fall in body temperature with a nadir at ∼100 minpostinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg - 1 I.P.), by systemic TRPV1 antagonism with capsazepine(40mg kg−1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kg−1 I.P.).However, CB1 receptor antagonism by rimonabant (4.6mg kg−1 I.P.) or SLV319 (15mg kg−1 I.P.)blocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant,the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEAdid not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermo effector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.
authors.affiliation: St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Steiner
authors.forename: Alla Y
authors.initials: AY
authors.lastname: Molchanova
authors.forename: M Devrim
authors.initials: MD
authors.lastname: Dogan
authors.forename: Shreya
authors.initials: S
authors.lastname: Patel
authors.forename: Erika
authors.initials: E
authors.lastname: Pétervári
authors.forename: Márta
authors.initials: M
authors.lastname: Balaskó
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Wanner
authors.forename: Justin
authors.initials: J
authors.lastname: Eales
authors.forename: Daniela L
authors.initials: DL
authors.lastname: Oliveira
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: M Camila
authors.initials: MC
authors.lastname: Almeida
authors.forename: Miklós
authors.initials: M
authors.lastname: Székely
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001892:Camphanes / Q000008:administration & dosage; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage; D063388:Endocannabinoids; D005260:Female; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides; D008297:Male; D010880:Piperidines / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: C482795:3-(4-chlorophenyl)-N-methyl-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine; D001095:Arachidonic Acids; D001892:Camphanes; C469526:Cnr2 protein, rat; D004224:Diterpenes; D063388:Endocannabinoids; D008070:Lipopolysaccharides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D013449:Sulfonamides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C440499:lipopolysaccharide, Escherichia coli O111 B4; C024353:resiniferatoxin; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin; C078814:anandamide