Post-traumatic stress disorder (PTSD) arises after tremendous traumatic experiences. Recently, we have reported that morphine has time-dependent protective effects against behavioral and morphological deficits in the single prolonged stress (SPS) as an experimental model of PTSD in adult male rats. To find the mechanisms underlying the protective effects of morphine against SPS-induced PTSD-like symptoms, the present study investigated the interaction between morphine and hypothalamic-pituitary-adrenal (HPA) axis and beta - adrenergic system, which crucially involved in the stress response, on PTSD-like symptoms in male rats. The animals were exposed to the SPS procedure (restraint for 2 h, forced swimming for 20 min, and ether anesthesia) and morphine (10 mg/kg) or saline was injected 24 h following the SPS. The glucocorticoid receptor antagonist RU486 (20 mg/kg), the mineralocorticoid receptor antagonist spironolactone (50 mg/kg), and the corticosterone synthesis inhibitor metyrapone (50 mg/kg) were injected 90 min before morphine administration to block the HPA axis activity. The beta - adrenergic receptor blocker propranolol (10 mg/kg) and the peripheral beta-adrenergic receptor blocker nadolol (5 mg/kg) were administered 30 min before morphine injection to block the beta - adrenergic system. Anxiety-like behaviors were evaluated using the elevated plus maze (EPM) 11 days after the SPS. After that, animals were conditioned in a fear-conditioning task and extinction training was performed on days 1, 2, 3, 4 and 11 after fear conditioning. SPS increased anxiety-like behaviors and impaired fear extinction. Morphine injection 24 h after SPS significantly improved anxiety-like behaviors and enhanced fear extinction. The RU486, spironolactone and metyrapone prevented the protective effects of morphine on both SPS-induced anxiety-like behaviors and impaired fear extinction. The propranolol, and nadolol did not prevent the effect of morphine on anxiety-like behaviors, but the propranolol prevented morphine effects on fear extinction in SPS animals.

These findings together suggest that the protective effects of morphine on PTSD-like symptoms in rats require a certain level of the HPA axis and central beta - adrenergic activity and any alteration in the function of these systems can impede the protective effects of morphine.

创伤后应激障碍 (PTSD) 出现在巨大的创伤经历之后。最近，我们报告说，作为成年雄性大鼠 PTSD 的实验模型，吗啡对单一长期应激 (SPS) 中的行为和形态缺陷具有时间依赖性保护作用。为了找到吗啡对 SPS 诱导的 PTSD 样症状的保护作用的潜在机制，本研究调查了吗啡与下丘脑 - 垂体 - 肾上腺 (HPA) 轴和β-肾上腺素能系统之间的相互作用，后者在应激反应中起着至关重要的作用，关于雄性大鼠的 PTSD 样症状。动物暴露于 SPS 程序（限制 2 小时，强迫游泳 20 分钟，乙醚麻醉）并在 SPS 后 24 小时注射吗啡（10 毫克/千克）或生理盐水。糖皮质激素受体拮抗剂 RU486 (20 mg/kg)、盐皮质激素受体拮抗剂螺内酯 (50 mg/kg) 和皮质酮合成抑制剂美替拉酮 (50 mg/kg) 在吗啡给药前 90 分钟注射以阻断 HPA 轴活性。β-肾上腺素能受体阻滞剂普萘洛尔（10mg/kg）和外周β-肾上腺素能受体阻滞剂纳多洛尔（5mg/kg）在吗啡注射前30分钟给药以阻断β-肾上腺素能系统。在 SPS 后 11 天使用高架十字迷宫 (EPM) 评估焦虑样行为。之后，动物接受恐惧条件反射任务，并在恐惧条件反射后的第 1、2、3、4 和 11 天进行灭绝训练。SPS 增加了类似焦虑的行为并削弱了恐惧消退。SPS 后 24 小时注射吗啡可显着改善焦虑样行为并增强恐惧消退。RU486、螺内酯和美替拉酮阻止吗啡对 SPS 诱导的焦虑样行为和恐惧消退受损的保护作用。普萘洛尔和纳多洛尔不能阻止吗啡对焦虑样行为的影响，但普萘洛尔阻止了吗啡对 SPS 动物的恐惧消退的影响。

这些发现共同表明，吗啡对大鼠 PTSD 样症状的保护作用需要一定水平的 HPA 轴和中枢 β-肾上腺素能活性，而这些系统功能的任何改变都会阻碍吗啡的保护作用。