关于内源性类阿片肽对于ACTH分泌影响的临床研究
摘要
本研究以血清N-POMC水平作为ACTH分泌的指标，观察了静脉注射大剂量(16mg)和小剂量(0.4mg)纳络酮对于正常人和柯兴氏病等垂体—肾上腺疾病患者ACTH和皮质醇基础分泌的影响；观察了纳络酮(25mg)对于正常人和柯兴氏病患者羊CRH1-41(100μg)兴奋后或胰岛素低血糖兴奋后ACTH和皮质醇分泌的影响。结果(1)：在8名正常人注射大剂量纳络酮后30、60和90分钟时，血清N-POMC和血浆皮质醇水平较生理盐水对照试验显著升高(P＜0.02～0.001)，但小剂量无效。5例阿迪森氏病和4例先天性肾上腺皮质增生症患者注射大剂量纳络酮后，血清N-POMC的反应与正常人相似，而血皮质醇水平无上升；小剂量纳络酮无效。但是，大、小剂量纳络酮均不能改变8例柯兴氏病或纳尔逊氏综合征患者血N-POMC和皮质醇水平。此结果提示：纳络酮对于ACTH分泌的作用是通过了对其不敏感的δ或κ阿片肽受体起效的。一般认为，纳络酮刺激ACTH和皮质醇分泌是通过解除类阿片肽对于下丘脑CRH神经元的抑制作用使内源性CRH释放增加起作用的。为什么柯兴氏病和纳尔逊氏综合征患者血ACTH对于纳络酮不起反应?是纳络酮未引起内源性CRH释放增加，抑或是垂体ACTH瘤对于增加的CRH不起反应，需要进一步研究来回答。(2)7例柯兴氏病患者对于羊CRH1—41的反应与6名正常人相似。血清N-POMC峰值在患者和正常人分别是基础值的2.0±0.3和2.0±0.2倍(P＞0.9)；血浆皮质醇峰值分别是基础的1.6±0.2和2.2±0.4倍(P＞0.9)。加用纳络酮后，柯兴氏病患者没有象正常人一样出现血N-POMC和皮质醇水平的进一步增高反应。结果说明外源性CRH不仅能够兴奋正常人的垂体ACTH细胞分泌，也能兴奋柯兴氏病患者垂体ACTH瘤细胞分泌ACTH。这就回答了上面的问题，不是柯兴氏病患者对于增加的内源性CRH不起反应，而是纳络酮未能引起内源性CRH的释放增加。这可能是因为在柯兴氏病患者高皮质醇血症和高ACTH血症更强烈地抑制着下丘脑CRH神经元的功能。(3)在5名正常人的研究发现胰岛素低血糖试验(RI0.15u／kg体重)中血N-POMC和皮质醇水平明显增高，最大增值分别是777±127pg／ml(P＜0.01)和17.6±1.5μg／d1(P＜0.001)。纳络酮和胰岛素低血糖联合应用时无相加作用。结果提示：纳络酮和胰岛素低血糖应激刺激ACTH分泌可能通过，至少是部分地通过相同的机制起效的，即通过解除内源性类阿片肽对于下丘脑—垂体—肾上腺轴的张力性抑制起效。但在柯兴氏病患者，无论是单纯胰岛素低血糖(RI0.30u／kg体重)还是胰岛素低血糖加纳络酮均不能改变其血N-POMC和皮质醇水平，可能此两(?)刺激均未能刺激内源性CRH释放增加。
从我们的研究结果，可以得出以下几点推论 (1) 纳络酮刺激正常人，阿迪森氏病和先天性肾上腺皮质增生症患者ACTH分泌的作用是经由对其相对不敏感的δ或κ受体实现的；(2) 胰岛素低血糖应激兴奋ACTH分泌可能涉及类阿片肽机制；(3) 柯兴氏病患者血N-POMC对于纳络酮、胰岛素低血糖刺激均无反应，间接说明其内源性CRH神经元功能处于受抑制状态，提示病人的垂体ACTH瘤不受内源性CRH的调控．是自主或相对自主的腺瘤。
We have used the serum N-POMC level as indication of ACTH secretion to test the effects of a low (0.4mg) and a high (16mg) dose of naloxone on the basal secretion oi ACTH and cortisol in normal subjects and patients with pituitary-adrenal disorders; to test the effect of naloxone on the responses of ACTH and cortisol to oCRH in seven patients with Cushing's disease and six normal subjects as controls; and to test the effect of naloxone on the release of ACTH stimulated by insulin—induced hypoglycemia in five normal subjects and five patients with Cushing's disease.
Results:(1) In eight normal subjects the high dose of naloxone caused obvious increases in serum N-POMC and cortisol concentrations at 30, 60 and 90 minute (p < 0.02-0.001) compared with that after injection of 0.9% saline, whereas the low dose of naloxone was ineffective. Similar response of blood N-POMC, not cortisol, to high dose of naloxone was found in five patients with Addison's disease and four patients with conjenital adrenal hyperplasia. But both doses of naloxone failed to influence blood N-POMC and cortisol levels in eight patients with ACTH-dependent Cushing's disease or Nelson's syndrome. These results suggest that inhibitory δ- or κ-opiate receptors (insensitive to naloxone) are involved in the regulation of ACTH secretion. In patients with Cusing's disease or Nelson's syndrome ACTH is not altered by naloxone.
(2). The peak values of serum N-POMC after intravenous injection of oCRH1-41(100ug) in controls and patients with Cushing's disease rose 2.0 ± 0.2 and2.0± 0.3 folds respectively which were not different from each other (p > 0.9), and the peak levels of plasma cortisol increased to the same extent as serum N-POMC which were 2.2 ± 0.4 and 1.6 ± 0.2 folds of their basal levels respectively. These results reflect that exogenous CRH can stimulate N-POMC and cortisol secretion both in normal subjects and patients with Cushing's disease. However, the additional injection of naloxone (25 mg) could cause further increases of blood N—POMC and cortisol only in normal subjects, but not in patients with Cushing's disease. Naloxone, by blooking the inhibitory effect of opioid peptides on CRH secretion, might cause an increase of N-POMC and cortisol in normal subjects.
(3). In normal subjects, insulin-induced hypoglycemia (0.15 u / kg) caused prompt increases in blood N-POMC and cortisol levels. The peak changes (peak values minus basal values) of N—POMC and cortisol during insulin— induced hypoglycemia were 777 ± 127 pg/ ml and 17.6± 1.5 ug/ dl respectively, which were unchanged by the additional injection of naloxone (25 mg). The effects of naloxone and insulin were not addictive. Thse results indicate that naloxone and the hypoglycemia—stress stimulated release of ACTH may act, at least in part, through common mechanisms, that is, through disinhibition of opiate inhibition on pituitary—adrenal axis. But in patients with Cushing's disease, both insulin—induced hypoglycemia (0.30 u/ kg) and naloxone could not alter the blood
从我们的研究结果，可以得出以下几点推论 (1) 纳络酮刺激正常人，阿迪森氏病和先天性肾上腺皮质增生症患者ACTH分泌的作用是经由对其相对不敏感的δ或κ受体实现的；(2) 胰岛素低血糖应激兴奋ACTH分泌可能涉及类阿片肽机制；(3) 柯兴氏病患者血N-POMC对于纳络酮、胰岛素低血糖刺激均无反应，间接说明其内源性CRH神经元功能处于受抑制状态，提示病人的垂体ACTH瘤不受内源性CRH的调控．是自主或相对自主的腺瘤。
We have used the serum N-POMC level as indication of ACTH secretion to test the effects of a low (0.4mg) and a high (16mg) dose of naloxone on the basal secretion oi ACTH and cortisol in normal subjects and patients with pituitary-adrenal disorders; to test the effect of naloxone on the responses of ACTH and cortisol to oCRH in seven patients with Cushing's disease and six normal subjects as controls; and to test the effect of naloxone on the release of ACTH stimulated by insulin—induced hypoglycemia in five normal subjects and five patients with Cushing's disease.
Results:(1) In eight normal subjects the high dose of naloxone caused obvious increases in serum N-POMC and cortisol concentrations at 30, 60 and 90 minute (p < 0.02-0.001) compared with that after injection of 0.9% saline, whereas the low dose of naloxone was ineffective. Similar response of blood N-POMC, not cortisol, to high dose of naloxone was found in five patients with Addison's disease and four patients with conjenital adrenal hyperplasia. But both doses of naloxone failed to influence blood N-POMC and cortisol levels in eight patients with ACTH-dependent Cushing's disease or Nelson's syndrome. These results suggest that inhibitory δ- or κ-opiate receptors (insensitive to naloxone) are involved in the regulation of ACTH secretion. In patients with Cusing's disease or Nelson's syndrome ACTH is not altered by naloxone.
(2). The peak values of serum N-POMC after intravenous injection of oCRH1-41(100ug) in controls and patients with Cushing's disease rose 2.0 ± 0.2 and2.0± 0.3 folds respectively which were not different from each other (p > 0.9), and the peak levels of plasma cortisol increased to the same extent as serum N-POMC which were 2.2 ± 0.4 and 1.6 ± 0.2 folds of their basal levels respectively. These results reflect that exogenous CRH can stimulate N-POMC and cortisol secretion both in normal subjects and patients with Cushing's disease. However, the additional injection of naloxone (25 mg) could cause further increases of blood N—POMC and cortisol only in normal subjects, but not in patients with Cushing's disease. Naloxone, by blooking the inhibitory effect of opioid peptides on CRH secretion, might cause an increase of N-POMC and cortisol in normal subjects.
(3). In normal subjects, insulin-induced hypoglycemia (0.15 u / kg) caused prompt increases in blood N-POMC and cortisol levels. The peak changes (peak values minus basal values) of N—POMC and cortisol during insulin— induced hypoglycemia were 777 ± 127 pg/ ml and 17.6± 1.5 ug/ dl respectively, which were unchanged by the additional injection of naloxone (25 mg). The effects of naloxone and insulin were not addictive. Thse results indicate that naloxone and the hypoglycemia—stress stimulated release of ACTH may act, at least in part, through common mechanisms, that is, through disinhibition of opiate inhibition on pituitary—adrenal axis. But in patients with Cushing's disease, both insulin—induced hypoglycemia (0.30 u/ kg) and naloxone could not alter the blood
引文
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