RESUMO
The neurohypophyseal hormones oxytocin (OT) and vasopressin (VP) are involved in behavioral, autonomic and neuroendocrine functions. Both peptides are synthesized in magnocellular neurons of paraventricular and supraoptic nuclei at hypothalamic level whose axons terminate in the neurohypophysis (NH), from where OT and VP are released into the systemic circulation. NH contains abundant nitric oxide (NO) synthase suggesting that NO plays a role in the release of these neuropeptides. The endocannabinoid system is present in magnocellular neurons of the hypothalamic neurohypophyseal system, and we have previously demonstrated that endocannabinoids modulate OT secretion at hypothalamic level. In the present work, we investigated the in vitro effect of the endocannabinoid anandamide (AEA) on OT and VP release from NH of untreated adult male rats and the involvement of NO in this action. Our results showed that AEA decreased OT and VP secretion from NH. AEA action was mediated by NO, since the inhibition of NO synthesis completely blocked this inhibitory effect. We found that cannabinoid receptor type 2 (CB2) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are involved in the inhibitory effect of AEA because AM630 and capsazepine, CB2 and TRPV1 antagonists respectively, but not AM251, a CB1 antagonist, blocked AEA effect at neurohypophyseal level. These findings revealed an interaction between endocannabinoid, nitric oxide and oxytocin/vasopressin systems that could be involved in the modulation of homeostatic, behavioral and reproductive processes.
Assuntos
Ácidos Araquidônicos/fisiologia , Endocanabinoides/fisiologia , Óxido Nítrico/fisiologia , Ocitocina/metabolismo , Neuro-Hipófise/metabolismo , Vasopressinas/metabolismo , Animais , Masculino , Alcamidas Poli-Insaturadas , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides/metabolismo , Técnicas de Cultura de TecidosRESUMO
Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
Assuntos
Ingestão de Alimentos/fisiologia , Inflamação/fisiopatologia , Leptina/fisiologia , Animais , Ácidos Araquidônicos/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Dieta , Gorduras na Dieta/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides , Endotoxinas/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicerídeos/fisiologia , Imuno-Histoquímica , Inflamação/induzido quimicamente , Interleucina-10/biossíntese , Interleucina-10/genética , Leptina/sangue , Lipopolissacarídeos/farmacologia , Masculino , Fosforilação , Ratos , Ratos Wistar , Receptor Tipo 4 de Melanocortina/biossíntese , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/fisiologia , Receptores de Interleucina-10/biossíntese , Receptores de Interleucina-10/genética , Receptores para Leptina/biossíntese , Receptores para Leptina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
Anandamide binds to cannabinoid receptors and plays several central and peripheral functions. The aim of this work was to study the possible role for this endocannabinoid in controlling sperm-oviduct interaction in mammals. We observed that bull sperm and bovine oviductal epithelial cells express cannabinoid receptors, CB1 and CB2, and fatty acid amide hydrolase, the enzyme that controls intracellular anandamide levels. A quantitative assay to determine whether anandamide was involved in bovine sperm-oviduct interaction was developed. R(+)-methanandamide, a non-hydrolysable anandamide analog, inhibited sperm binding to and induced sperm release from oviductal epithelia. Selective CB1 antagonists (SR141716A or AM251) completely blocked R(+)-methanandamide effects. However, SR144528, a selective CB2 antagonist, did not exert any effect, indicating that only CB1 was involved in R(+)-methanandamide effect. This effect was not caused by inhibition of the sperm progressive motility or by induction of the acrosome reaction. Overall, our findings indicate for the first time that the endocannabinoid system is present in bovine sperm and oviductal epithelium and that anandamide modulates the sperm-oviduct interaction, by inhibition of sperm binding and induction of sperm release from oviductal epithelial cells, probably by activating CB1 receptors.
Assuntos
Ácidos Araquidônicos/fisiologia , Tubas Uterinas/metabolismo , Interações Espermatozoide-Óvulo/fisiologia , Espermatozoides/metabolismo , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Western Blotting/métodos , Canfanos/farmacologia , Carbamatos/farmacologia , Bovinos , Endocanabinoides , Epitélio/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Microscopia de Fluorescência , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Motilidade dos Espermatozoides/efeitos dos fármacos , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacosRESUMO
Anandamide (AEA) has been reported to have pleiotropic effects on reproduction, but the mechanism by which it exerts these effects is unclear. The aim of this study is to characterize rat placental endocannabinoid system and to analyze the possible functional role of AEA in the regulation of NO levels in rat placenta during pregnancy. We found that cannabinoids receptors (CB1 and CB2), FAAH and TRPV1 were expressed in chorio-allantoic placenta. NOS activity peaked at day 13 and decreased with progression of pregnancy. Both exogenous and endogenous AEA significantly decreased NOS activity. Although pre-incubation with AM251 (CB1 antagonist) or AM630 (CB2 antagonist) had no effect, co-incubation with both antagonists induced NOS activity. Furthermore, pre-incubation with exogenous AEA and both antagonists resulted in the induction of placental NOS activity and this effect was reverted with capsazepine (selective TRPV1 antagonist). Additionally, the enhanced NO synthesis caused by capsaicin was abrogated by co-treatment with capsazepine, illustrating that NOS activity could be modulated by TRPV1. Finally, the inhibition of TRPV1 receptor by capsazepine caused a significant fall in NOS activity. These data support the concept that AEA modulates NO levels by two independent pathways: (1) diminishing the NOS activity via CBs; and (2) stimulating NO synthesis via TRPV1. We hypothesized that AEA have an important implication in the normal function of placental tissues.
Assuntos
Ácidos Araquidônicos/farmacologia , Óxido Nítrico/biossíntese , Placenta/efeitos dos fármacos , Placenta/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Animais , Ácidos Araquidônicos/fisiologia , Moduladores de Receptores de Canabinoides/metabolismo , Moduladores de Receptores de Canabinoides/farmacologia , Endocanabinoides , Feminino , Indometacina/farmacologia , Óxido Nítrico Sintase/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/fisiologia , Canais de Cátion TRPV/metabolismo , Tocolíticos/farmacologiaRESUMO
The purpose of this review is to present an update on the role of arachidonic acid and its metabolites, the "eicosanoids", in the inflammatory response. In order to make this a more comprehensive and concise article, I have emphasized the origin and fate of these biologically active products, rather than explain complex biochemical reactions. Consideration is given to mechanisms of action of anti-inflammatory agents currently in use and, to some extent, to the most revolutionary approach, namely lipid mediators and dietary manipulation. Hopefully, the current knowledge, will provide a basis for better understanding of the pathogenesis of rheumatic diseases, and in so doing, will open new avenues for the treatment of systemic inflammatory diseases.
Assuntos
Ácidos Araquidônicos/fisiologia , Inflamação/fisiopatologiaAssuntos
Ácidos Araquidônicos/metabolismo , Leucotrienos , Resistência das Vias Respiratórias , Ácidos Araquidônicos/biossíntese , Ácidos Araquidônicos/classificação , Ácidos Araquidônicos/fisiologia , Quimiotaxia de Leucócito , Humanos , Ácidos Hidroxieicosatetraenoicos/biossíntese , Ácidos Hidroxieicosatetraenoicos/fisiologia , Inflamação , Leucotrieno B4/biossíntese , Leucotrieno B4/fisiologia , Lipoxigenase/metabolismo , Conformação Molecular , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/biossíntese , Prostaglandinas/fisiologia , SRS-A/biossíntese , SRS-A/fisiologia , Terminologia como Assunto , Sistema Vasomotor/fisiologiaRESUMO
Los conocimientos actuales sobre las funciones biológicas que cumplen los derivados del ácido araquidónico justifican esta revisión, la cual incluye aspectos de denominación, biosíntesis, mecanismo de acción y degradación. La participación de las prostaglandinas, tromboxanos y leucotrioenos en fenómenos de regulación funcional de endotelios vasculares, plaquetas, músculo liso, secreción glandular y leucocitos han sido estudiados en forma tal que ha sido posible la interpretación de la fisiología a diferentes niveles. Derivado de este conocimiento también ha sido posible establecer el papel de estos compuestos en situaciones patológicas. El proceso inflamatorio se analiza con detención con el conocer la participación de los derivados del ácido araquidónico y establecer su rol en enfermedades caracterizadas por inflamación