ABSTRACT
We previously reported that endothelin-1 (ET-1) reduced the frequency of spontaneous excitatory currents in vasopressinergic magnocellular cells through the activation of endothelin ETA receptors in rat brain slices. This effect was abolished by a cannabinoid CB1 receptor antagonist, suggesting the involvement of endocannabinoids. The present study investigated whether the blockade of ETA or CB1 receptors during the phase of increased levels of ET-1 after severe sepsis increases the survival rate of animals concomitantly with an increase in plasma arginine vasopressin (AVP) levels. Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). Treatment with the CB1 receptor antagonist rimonabant (Rim; 10 and 20âmg/kg, orally) 4âh after CLP (three punctures) significantly increased the survival rate compared with the CLP per vehicle group. Intracerebroventricular treatment with the ETA receptor antagonist BQ123 (100 pmol) or with Rim (2âµg) 4 and 8âh after CLP but not the ETB receptor antagonist BQ788 (100 pmol), also significantly improved the survival rate. Sham-operated and CLP animals that were treated with Rim had significantly lower core temperature than CLP animals. However, oral treatment with Rim did not change bacterial count in the peritoneal exudate, neutrophil migration to the peritoneal cavity, leucopenia or increased plasma interleukin-6 levels induced by CLP. Both Rim and BQ123 also increased AVP levels 12âh after CLP. The blockade of central CB1 and ETA receptors in the late phase of sepsis increased the survival rate, reduced body temperature and increased the circulating AVP levels.
Subject(s)
Arginine Vasopressin/metabolism , Receptor, Cannabinoid, CB1/metabolism , Receptor, Endothelin A/metabolism , Sepsis/metabolism , Animals , Arginine Vasopressin/blood , Cecum/injuries , Interleukin-6/blood , Ligation , Male , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/blood , Receptor, Endothelin A/blood , Sepsis/blood , Sepsis/etiologyABSTRACT
The present study investigated the effects of the ethanolic extract (ESa), fractions, and compounds isolated from Sinningia aggregata in male Swiss mice on carrageenan-induced paw edema, neutrophil migration, mechanical hyperalgesia, formalin-induced nociception, and lipopolysaccharide-induced fever. The ESa did not alter edema, neutrophil migration, or fever at any of the doses tested. However, the ESa reduced phase II of formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The petroleum ether (PE) and ethyl acetate (EA) fractions and aggregatin D (AgD; isolated from the EA fraction) reduced formalin-induced nociception. Anthraquinones from the PE fraction were ineffective. AgD also inhibited carrageenan-induced mechanical hyperalgesia. Neither the ESa nor AgD altered thermal nociception or motor performance. Local administration of AgD also reduced hyperalgesia induced by carrageenan, bradykinin, tumor necrosis factor-α, interleukin-1ß, cytokine-induced neutrophil chemoattractant, prostaglandin E2, and dopamine but not hyperalgesia induced by forskolin or dibutyryl cyclic adenosine monophosphate. The positive control dipyrone reduced the response induced by all of the stimuli. Additionally, glibenclamide abolished the analgesic effect of dipyrone but not the one induced by AgD. AgD did not change lipopolysaccharide-induced nitric oxide production by macrophages or the nociception induced by capsaicin, cinnamaldehyde, acidified saline, or menthol. These results suggest that the ESa has important antinociceptive activity, and this activity results at least partially from the presence of AgD. AgD reduced mechanical hyperalgesia induced by several inflammatory mediators through mechanisms that are different from classic analgesic drugs.
Subject(s)
Analgesics/pharmacology , Lamiales/chemistry , Naphthoquinones/pharmacology , Nociception/drug effects , Plant Extracts/pharmacology , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Hot Temperature , Hyperalgesia/drug therapy , Macrophages/drug effects , Male , Mice , Naphthoquinones/chemistry , Naphthoquinones/therapeutic use , Neutrophils/drug effects , Plant Extracts/chemistry , Plant Extracts/therapeutic use , TouchABSTRACT
This study compared the involvement of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) within the central nervous system (CNS) in the febrile response induced by zymosan (zym) and lipopolysaccharide (LPS). In addition, we investigated whether zym could activate important regions related to fever; namely, the vascular organ of the laminae terminalis (OVLT) and the median preoptic nucleus (MnPO). Intraperitoneal injection of zym (1, 3, and 10 mg/kg) induced a dose-related increase in core temperature. Zym (3 mg/kg) also reduced tail skin temperature, suggesting the activation of heat conservation mechanisms, as expected, during fever. LPS increased plasma levels of TNF-α measured at 1 h, IL-1ß measured at 2 h, and IL-6 measured at 3 h after injection. Zym increased circulating levels of IL-6 but not those of TNF-α or IL-1ß at the same time points. In addition, an intracerebroventricular injection of antibodies against TNF-α (2.5 µg) and IL-6 (10 µg) or the IL-1 receptor antagonist (160 ng) reduced the febrile response induced by zym and LPS. Zym (100 µg/ml) also increased intracellular calcium concentration in the OVLT and MnPO from rat primary neuroglial cultures and increased release of TNF-α and IL-6 into the supernatants of these cultures. Together, these results suggest that TNF-α, IL-1ß, and IL-6 within the CNS participate in the febrile response induced by zym. However, the time course of release of these cytokines may be different from that of LPS. In addition, zym can directly activate the brain areas related to fever.