RESUMO
Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic-pituitary-adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.
Assuntos
Cardiotônicos/uso terapêutico , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Dependência de Morfina/tratamento farmacológico , Antagonistas de Entorpecentes/efeitos adversos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Abstinência a Substâncias/prevenção & controle , Animais , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Dependência de Morfina/fisiopatologia , Naloxona/efeitos adversos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Fosforilação/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Síndrome de Abstinência a Substâncias/etiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/prevenção & controle , Aumento de Peso/efeitos dos fármacosRESUMO
Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3-4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment (p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.