Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) recepto...

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Bibliographic Details
Published in:American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2013-08, Vol.305 (3), p.R224-R231
Main Authors: Duncan, Marnie, Galic, Michael A, Wang, Arthur, Chambers, Adam P, McCafferty, Donna-Marie, McKay, Derek M, Sharkey, Keith A, Pittman, Quentin J
Format: Article
Language:English
Subjects:
Animals
Body Temperature - physiology
Cytokines
Cytokines - biosynthesis
Data Interpretation, Statistical
Fever - chemically induced
Fever - physiopathology
Hyperalgesia - chemically induced
Hyperalgesia - genetics
Immune system
Immunity, Innate - physiology
Lipopolysaccharides - pharmacology
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Pain Measurement
Piperidines - pharmacology
Poly I-C - pharmacology
Proto-Oncogene Proteins c-fos - biosynthesis
Pyrazoles - pharmacology
Real-Time Polymerase Chain Reaction
Receptor, Cannabinoid, CB1 - antagonists & inhibitors
Receptor, Cannabinoid, CB1 - genetics
Receptor, Cannabinoid, CB1 - physiology
Ribonucleic acid
RNA
RNA - biosynthesis
RNA - isolation & purification
Rodents
Toll-Like Receptor 3 - drug effects
Toll-Like Receptor 4 - agonists
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Summary:Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1(-/-)) mice did not display LPS-evoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1(-/-) mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1(-/-) mice. Liver and spleen TLR4 mRNA were significantly lower in CB1(-/-) mice compared with wild-type mice, and peritoneal macrophages from CB1(-/-) mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production.
ISSN:0363-6119
1522-1490
DOI:10.1152/ajpregu.00104.2013