Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators

• Endocannabinoids participate in the fever induced by TNF, IL-1β, IL-6, CRF and ET-1.
• Endocannabinoids are not involved in the fever induced by PGE2 or PGF2α.
• Anandamide induces fever dependent on the synthesis of prostaglandin and opioids.

This study aims to explore the contribution of endocannabinoids on the cascade of mediators involved in LPS-induced fever and to verify the participation of prostaglandins and endogenous opioids in fever induced by anandamide (AEA). Body temperature (Tc) of male Wistar rats was recorded over 6 h, using a thermistor probe. Cerebrospinal fluid concentration of PGE2 and β-endorphin were measured by ELISA after the administration of AEA.Intracerebroventricular administration of the CB1 receptor antagonist AM251 (5 μg, i.c.v.), reduced the fever induced by IL-1β (3 ng, i.c.v.), TNF-α (250 ng, i.c.v.), IL-6 (300 ng, i.c.v.), corticotrophin release factor (CRH; 2.5 μg, i.c.v.) and endothelin (ET)-1 (1 pmol, i.c.v.), but not the fever induced by PGE2 (250 ng, i.c.v.) or PGF2α (250 ng, i.c.v.). Systemic administration of indomethacin (2 mg kg−1, i.p.) or celecoxib (5 mg kg−1, p.o.) reduced the fever induced by AEA (1 μg, i.c.v.), while naloxone (1 mg kg−1, s.c.) abolished it. The increases of PGE2 and β-endorphin concentration in the CSF induced by AEA were abolished by the pretreatment of rats with AM251.These results suggest that endocannabinoids are intrinsically involved in the pyretic activity of cytokines (IL-1β, TNF-α, IL-6), CRH and ET-1 but not the PGE2 or PGF2α induced fevers. However, anandamide via CB1 receptor activation induces fever that is dependent on the synthesis of prostaglandin and opioids.