McNally G P, Akil H
Mental Health Research Institute, The University of Michigan, Ann Arbor, MI, USA.
Neuroscience. 2002;112(3):605-17. doi: 10.1016/s0306-4522(02)00105-7.
The extra-hypothalamic actions of corticotropin-releasing hormone (CRH) have been accorded an important role in coordinating responses to stressors and contributing to the consequences of drug abuse. Recent proposals suggest that CRH actions in the bed nucleus of the stria terminalis coordinate responses to tonic/unpredictable stressors whereas these actions in the central nucleus of the amygdala coordinate responses to phasic/predictable stressors. We used in situ hybridization histochemistry and site-specific microinjections of a CRH receptor antagonist to study the role of CRH in opiate withdrawal. Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed significant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal). An increase of CRH mRNA in the paraventricular nucleus of the hypothalamus was specific to rats undergoing withdrawal. Intracerebroventricular microinjection of the CRH receptor antagonist, alpha(h)CRH(9-41), reduced the severity of opiate withdrawal. Microinjections of alpha(h)CRH(9-41) into the central nucleus of the amygdala also reduced the severity of withdrawal whereas bed nucleus of the stria terminalis microinjections of alpha(h)CRH(9-41) were without effect. These experiments provide evidence for a role of amygdala, but not bed nucleus of the stria terminalis, CRH in opiate dependence. We propose a specific role for down-regulation of opiate receptor signaling in increased expression of the CRH gene in the amygdala. Moreover, we suggest that the roles accorded to CRH in the bed nucleus of the stria terminalis versus amygdala in coordinating responses to stressors may need to be reconsidered to distinguish between external and internal/interoceptive stressors.
促肾上腺皮质激素释放激素（CRH）的下丘脑外作用在协调对应激源的反应以及导致药物滥用后果方面发挥着重要作用。最近的研究表明，终纹床核中的CRH作用可协调对持续性/不可预测应激源的反应，而杏仁核中央核中的这些作用则可协调对阶段性/可预测应激源的反应。我们采用原位杂交组织化学和CRH受体拮抗剂的位点特异性微量注射技术，研究CRH在阿片类药物戒断中的作用。经历阿片类药物戒断的大鼠表现出明显的行为和自主神经变化，伴有痛觉过敏和血浆皮质酮水平升高。CRH mRNA的原位杂交显示，在长期接受吗啡预处理、注射纳洛酮或两者兼有的大鼠（诱发戒断）中，杏仁核中央核中的CRH mRNA显著增加，而终纹床核中的CRH mRNA没有增加。下丘脑室旁核中CRH mRNA的增加是经历戒断的大鼠所特有的。脑室内微量注射CRH受体拮抗剂α（h）CRH（9 - 41）可减轻阿片类药物戒断的严重程度。向杏仁核中央核微量注射α（h）CRH（9 - 41）也可减轻戒断的严重程度，而向终纹床核微量注射α（h）CRH（9 - 41）则没有效果。这些实验为杏仁核而非终纹床核中的CRH在阿片类药物依赖中的作用提供了证据。我们提出，阿片受体信号下调在杏仁核中CRH基因表达增加中具有特定作用。此外，我们认为，可能需要重新考虑CRH在终纹床核和杏仁核中协调对应激源反应时所起的作用，以区分外部应激源和内部/内感受性应激源。
