Sickness behaviours are host defence adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviours include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate lipopolysaccharide (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 to wild-type, and peritoneal macrophages from CB₁^-/- mice did not release pro-inflammatory 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.

PMID:

 23739343
[PubMed – as supplied by publisher]http://www.ncbi.nlm.nih.gov/pubmed/23739343