Papaleo Francesco, Kitchener Pierre, Contarino Angelo
Laboratoire Homéostasie-Allostasie-Pathologie, EA 3666, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Neuron. 2007 Feb 15;53(4):577-89. doi: 10.1016/j.neuron.2007.01.022.
Escape from the extremely stressful opiate withdrawal syndrome may motivate opiate seeking and taking. The corticotropin-releasing factor receptor-1 (CRF1) pathway mediates behavioral and endocrine responses to stress. Here, we report that genetic inactivation (CRF1-/-) as well as pharmacological antagonism of the CRF/CRF1 receptor pathway increased and prolonged the somatic expression of opiate withdrawal. Opiate-withdrawn CRF1-/- mice also showed aberrant CRF and dynorphin expression in the paraventricular nucleus of the hypothalamus (PVN) and the striatum, indicating profound impairments in stress-responsive brain circuitry. Intake of nonstressful amounts of corticosterone effectively reduced the exaggerated somatic reactions of CRF1-/- mice to opiate withdrawal. Exogenous corticosterone also restored "wild-type-like" patterns of CRF and dynorphin gene expression in the PVN and the striatum of opiate-withdrawn CRF1-/- mice, respectively. The present findings unravel a key role for the hypothalamus-pituitary-adrenal (HPA) system and brain extra-hypothalamic CRF/CRF1 receptor circuitry in somatic, molecular, and endocrine alterations induced by opiate withdrawal.
摆脱极度紧张的阿片类药物戒断综合征可能会促使人们寻找和使用阿片类药物。促肾上腺皮质激素释放因子受体-1（CRF1）通路介导对应激的行为和内分泌反应。在此，我们报告基因失活（CRF1-/-）以及CRF/CRF1受体通路的药理学拮抗作用会增加并延长阿片类药物戒断的躯体表现。阿片类药物戒断的CRF1-/-小鼠在下丘脑室旁核（PVN）和纹状体中还表现出CRF和强啡肽表达异常，表明应激反应性脑回路存在严重损伤。摄入无应激剂量的皮质酮可有效降低CRF1-/-小鼠对阿片类药物戒断的过度躯体反应。外源性皮质酮还分别恢复了阿片类药物戒断的CRF1-/-小鼠PVN和纹状体中CRF和强啡肽基因表达的“野生型样”模式。本研究结果揭示了下丘脑-垂体-肾上腺（HPA）系统和脑内下丘脑外CRF/CRF1受体回路在阿片类药物戒断引起的躯体、分子和内分泌改变中的关键作用。
