Group of Cellular and Molecular Pharmacology, Department of Pharmacology, School of Medicine, University of Murcia, Murcia, Spain.
PLoS One. 2012;7(2):e31119. doi: 10.1371/journal.pone.0031119. Epub 2012 Feb 15.
Experimental and clinical findings have shown that administration of adrenoceptor antagonists alleviated different aspects of drug withdrawal and dependence. The present study tested the hypothesis that changes in CREB activation and phosphorylated TORC1 levels in the hypothalamic paraventricular nucleus (PVN) after naloxone-precipitated morphine withdrawal as well as the HPA axis activity arises from α(1)- and/or β-adrenoceptor activation. The effects of morphine dependence and withdrawal on CREB phosphorylation (pCREB), phosphorylated TORC1 (pTORC1), and HPA axis response were measured by Western-blot, immunohistochemistry and radioimmunoassay in rats pretreated with prazosin (α(1)-adrenoceptor antagonist) or propranolol (β-adrenoceptor antagonist). In addition, the effects of morphine withdrawal on MHPG (the main NA metabolite at the central nervous system) and NA content and turnover were evaluated by HPLC. We found an increase in MHPG and NA turnover in morphine-withdrawn rats, which were accompanied by increased pCREB immunoreactivity and plasma corticosterone concentrations. Levels of the inactive form of TORC1 (pTORC1) were decreased during withdrawal. Prazosin but not propranolol blocked the rise in pCREB level and the decrease in pTORC1 immunoreactivity. In addition, the HPA axis response to morphine withdrawal was attenuated in prazosin-pretreated rats. Present results suggest that, during acute morphine withdrawal, NA may control the HPA axis activity through CREB activation at the PVN level. We concluded that the combined increase in CREB phosphorylation and decrease in pTORC1 levels might represent, in part, two of the mechanisms of CREB activation at the PVN during morphine withdrawal.
实验和临床研究结果表明，肾上腺素受体拮抗剂的给药缓解了药物戒断和依赖的不同方面。本研究检验了这样一个假设，即在纳洛酮引发的吗啡戒断后，下丘脑室旁核（PVN）中 CREB 激活和磷酸化 TORC1 水平的变化以及 HPA 轴活性源于 α(1)-和/或β-肾上腺素受体的激活。通过 Western blot、免疫组织化学和放射免疫测定法，在预先用哌唑嗪（α(1)-肾上腺素受体拮抗剂）或普萘洛尔（β-肾上腺素受体拮抗剂）预处理的大鼠中测量吗啡依赖和戒断对 CREB 磷酸化（pCREB）、磷酸化 TORC1（pTORC1）和 HPA 轴反应的影响。此外，通过 HPLC 评估吗啡戒断对 MHPG（中枢神经系统中去甲肾上腺素的主要代谢物）和去甲肾上腺素含量和周转率的影响。我们发现吗啡戒断大鼠的 MHPG 和去甲肾上腺素周转率增加，同时伴有 pCREB 免疫反应性和血浆皮质酮浓度增加。TORC1 的无活性形式（pTORC1）的水平在戒断期间下降。哌唑嗪但不是普萘洛尔阻断了 pCREB 水平的升高和 pTORC1 免疫反应性的降低。此外，在预先用哌唑嗪处理的大鼠中，HPA 轴对吗啡戒断的反应减弱。目前的结果表明，在急性吗啡戒断期间，NA 可能通过 PVN 水平的 CREB 激活来控制 HPA 轴活性。我们得出结论，在吗啡戒断期间，pCREB 磷酸化的联合增加和 pTORC1 水平的降低可能部分代表 CREB 在 PVN 激活的两种机制之一。
