J Physiol. 2011 Mar 14. [Epub ahead of print]
The hypothermic response to bacterial lipopolysaccharide critically depends on brain CB1, but not CB2 or TRPV1, receptors.
Steiner AA, Molchanova AY, Dogan MD, Patel S, Petervari E, Balasko M, Wanner SP, Eales J, Oliveira DL, Gavva NR, Almeida MC, Szekely M, Romanovsky AA.
Albany College of Pharmacy & Health Sciences, Albany, NY, USA;
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 min postinjection. 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 (40 mg 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 (4.6 mg kg(-1) I.P.) or SLV319 (15 mg 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 tumor necrosis factor-a. In contrast to rimonabant, the I.C.V. administration of AEA (50 µg) enhanced LPS hypothermia. Importantly, I.C.V. AEA did not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermoeffector 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. |
