RESUMO
Lipopolysaccharide (LPS) induces the production of inflammatory cytokines in the serum and brain; morphine has been shown to be immunosuppressive. However, we previously reported that serum levels of LPS-induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are potentiated during morphine tolerance due to the HPA axis desensitization. In this study, we examined LPS-induced cytokine production in the brain of morphine-tolerant rats. The animals were implanted with two and four morphine (75 mg) pellets on days 1 and 2, respectively. On either day 4 or 5, 250 microg/kg LPS was administered (i.p.). Animals implanted with placebo and injected with saline were used as the control. The animals were sacrificed either 16 or 2 h post-injection, respectively, and TNF-alpha, IL-1beta, and IL-6 mRNA levels in the brain were determined by reverse transcriptase polymerase chain reaction. IL-1beta mRNA increased 2 h post-LPS treatment, whereas IL-6 decreased. At 16 h, TNF-alpha expression mRNA increased. These data suggest that the inflammatory response in the brain is heightened during morphine tolerance.
Assuntos
Encéfalo/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Tolerância a Medicamentos/imunologia , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Animais , Encéfalo/imunologia , Citocinas/biossíntese , Sistema Imunitário/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/biossíntese , Interleucina-1beta/efeitos dos fármacos , Interleucina-6/biossíntese , Lipopolissacarídeos/toxicidade , Masculino , RNA Mensageiro/análise , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
Abnormalities in brain chemistry induced by acute or chronic treatment with LPS were studied in the rat model. Ex vivo brain metabolites were measured using proton magnetic resonance spectroscopy, whereas serum corticosterone levels were determined using radioimmunoassay. We observed increased lactate levels in all measured brain regions and decreased choline in the hypothalamus after chronic LPS treatment. Acute LPS treatment led to an elevation of corticosterone, whereas chronic LPS treatment led to attenuation of the HPA response. These findings suggest that chronic inflammation induced by LPS could lead to cell loss/dysfunction, and hence, desensitization of the HPA axis, particularly in the hypothalamus.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Endotoxinas/administração & dosagem , Espectroscopia de Ressonância Magnética , Animais , Colina/metabolismo , Corticosterona/sangue , Esquema de Medicação , Endotoxinas/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lactatos/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Masculino , Prótons , Radioimunoensaio , Ratos , Ratos Sprague-DawleyRESUMO
Using short- and long-course lipopolysaccharide (LPS) treatment regimens to induce endotoxin tolerance in rats, we compared TNF-alpha, IL-1beta, and IL-6 expression in the brain and serum following a LPS challenge. Serum corticosterone was also examined to evaluate the function of the hypothalamic-pituitary-adrenal (HPA) axis. We found that, during endotoxin tolerance, LPS-induced cytokine expression still occurred in the brain even when cytokines in the periphery were no longer induced, and that this differential cytokine expression may be mediated by corticosterone, a stress hormone and an anti-inflammatory agent.
