吗啡对下丘脑-垂体-肾上腺皮质轴的调节及研究进展

滥用毒品对身体的损害是多方面的 ,其中对内分泌的影响可能是最严重最深远的问题之一。下丘脑 -垂体 -肾上腺皮质轴（ｈｙｐｏｔｈａｌａｍｕｓ＿ｐｉｔｕｉｔａｒｙ-ａｄｒｅｎｏｃｏｒｔｉｃａｌａｘｉｓ,ＨＰＡＡ）是机体主要的内分泌系统 ,在应激反应中有重要作用。吗啡可调节ＨＰＡＡ的功能 ,影响机体的应激反应。然而 ,吗啡对ＨＰＡＡ功能的影响及机制仍是一个不解之谜。近年的研究结果表明 ,吗啡对ＨＰＡＡ功能有兴奋和抑制双重调节 ,效应的不同与吗啡的给药方式（急性和慢性给药）、给药剂量及给药对象（人和大鼠）有关 ,也与吗啡…     

鞘内注射吗啡对大鼠细胞免疫功能及皮质酮的影响

目的观察大鼠鞘内注射吗啡后植物血凝素（PHA）-诱导的脾淋巴细胞增殖反应和血清皮质酮的改变及米非司酮（RU486）预处理后对其的影响。方法24只雄性健康SD大鼠随机分为3组（n=8）：对照组（NS）、吗啡组（M）、RU486预注组（RU486组）,分别鞘内注射生理盐水50μl,吗啡40μg／50μl和吗啡40μg,RU486组鞘内注射前30min前腹腔注入RU48620mg／kg。给药6h后抽取血样并取出脾脏制成单细胞悬液。用四氮唑蓝比色（MTT）法测定PHA-诱导的大鼠脾淋巴细胞增殖反应,用酶联免疫法（EIA法）测定血清皮质酮浓度。结果与NS组比较,M组大鼠PHA-诱导的脾淋巴细胞增殖指数明显降低（P〈0．01）,血清皮质酮的浓度明显升高（P〈0．01）;与M组比较,RU486组PHA-诱导的脾淋巴细胞增殖指数无明显变化（P〉0．05）,与NS组和M组比较,RU486组血清皮质酮浓度均升高（P〈0．05）。结论鞘内注射吗啡可抑制大鼠细胞免疫功能;下丘脑-垂体-肾上腺（HPA）轴不参与此过程的调节。     

东莨菪碱对吗啡依赖大鼠下丘脑—垂体—性轴和肾上腺轴的影响

应用放射免疫法测定血浆黄体生成素（ＬＨ）、促卵泡刺激素（ＦＳＨ）、睾酮、泌乳素（ＰＲＬ）、促肾上腺皮质激素（ＡＣＴＨ）、皮质醇含量。结果显示吗啡依赖大鼠血浆性轴激素ＬＨ和睾酮含量较正常对照组降低，而肾上腺轴激素ＡＣＴＨ含量降低，皮质醇含量升高。经纳洛酮激发戒断反应时，血浆睾酮，ＰＲＬ，ＡＣＴＨ含量升高，在纳洛酮激发前半小时注射东莨菪碱（０．５ｍｇ／ｋｇ），大鼠血浆皮质醇和睾酮含量降低。自然戒断组经东莨菪碱治疗６天后，血浆ＦＳＨ，ＰＲＬ，ＡＣＴＨ和皮质醇含量可恢复正常，而血浆睾酮含量明显升高。结果表明东莨菪碱急性或慢性处理对吗啡依赖大鼠血浆下丘脑┐垂体┐性轴和下丘脑┐垂体┐肾上腺轴的激素水平的紊乱有一定的治疗作用。     

阿片类物质与下丘脑-垂体-肾上腺皮质轴

阿片依赖是一种慢性、反复发作性脑疾病。本文综述了阿片类物质依赖、戒断和复吸各个阶段下丘脑-垂体-肾上腺皮质轴的改变,及其与阿片依赖、戒断和复吸的关系。     

地塞米松对卵蛋白所致哮喘大鼠下丘脑-垂体-肾上腺皮质轴及骨代谢的影响

目的：观察地塞米松对卵蛋白（Ovalbumin,OVA）所致哮喘大鼠的不同阶段（撤停前、撤停中、撤停后）下丘脑-垂体-肾上腺皮质轴（HPA轴）及骨代谢的影响。方法：90只大鼠随机分为正常对照组、哮喘模型组和地塞米松干预组,每组30只。每组根据处死时间的不同（实验第49、77、91天）随机各分为3个亚组,每组10只。以卵蛋白注射致敏结合卵蛋白雾化激发的方法建立大鼠哮喘模型。实验第35天开始,地塞米松干预组大鼠腹腔注射地塞米松0.5mg/kg,至实验第48天（撤停前阶段）;第49天开始按照每周0.1mg/kg的剂量递减地塞米松用量,至实验第76天（撤停中阶段）;第77天停用地塞米松,观察至实验第90天（撤停后阶段）。哮喘模型组及地塞米松干预组同时每周2次给予1%OVA生理盐水溶液雾化吸入。检测不同阶段各组大鼠脾脏及肾上腺指数、血清皮质酮（CORT）、血浆促肾上腺皮质激素（ACTH）、下丘脑促肾上腺皮质激素释放激素（CRH）及血浆骨钙素（BGP）含量。结果：（1）第49天,正常对照组、哮喘模型组、地塞米松干预组大鼠脾脏指数分别为1.504±0.213、1.548±0.208、1.254±0.239,肾上腺指数分别为0.132±0.039、0.108±0.027、0.065±0.017,CORT含量分别为（2301±628）、（1658±486）和（235±160）ng/L,ACTH含量分别为（62.7±17.4）、（32.7±17.2）和（19.7±8.8）ng/L,CRH含量分别为（5.77±2.01）、（4.20±1.87）和（3.40±1.28）ng/（mg.prot）,BGP含量分别为（5.22±2.14）、（3.64±1.40）和（0.65±0.62）μg/L。哮喘模型组ACTH及CRH含量均明显低于正常对照组（P（0.01,P（0.05）;地塞米松干预组CRH含量明显低于正常对照组,其他各项指标明显低于正常对照组和哮喘模型组（均P〈0.01）。（2）第77天,正常对照组、哮喘模型组、地塞米松干预组大鼠脾脏指数分别为1.515±0.169、1.567±0.180）、1.287±0.380,肾上腺指数分别为0.112±0.058、0.100±0.027、0.069±0.022,CORT含量分别为（2433±379）、（1905±410）和（355±239）ng/L,ACTH含量分别为（65.3±31.0）、（38.4±11.7）和（39.6±14.9）ng/L,CRH含量分别为（5.05±1.62）、（4.15±1.39）和（3.04±1.37）ng/（mg.prot）,BGP含量分别为（2.63±0.96）、（2.50±1.20）和（0.79±0.53）μg/L。哮喘模型组CORT含量明显低于正常对照组（P〈0.01）;地塞米松干预组除ACTH外其他各项指标均明显低于正常对照组和哮喘模型组（P〈0.05或0.01）。（3）第91天,正常对照组、哮喘模型组、地塞米松干预组大鼠脾脏指数分别为1.463±0.190、1.786±0.316、2.278±0.412,肾上腺指数分别为0.112±0.021、0.110±0.020、0.093±0.017,CORT含量分别为（2627±509）、（2318±364）和（2212±400）ng/L,ACTH含量分别为（63.0±33.5）、（48.8±19.9）和（30.7±19.1）ng/L,CRH含量分别为（5.39±1.40）、（3.80±0.94）和（3.67±1.09）ng/（mg.prot）,BGP含量分别为（4.58±2.19）、（3.21±1.34）和（1.93±0.91）μg/L。哮喘模型组脾脏指数明显高于正常对照组（P〈0.01）,CRH含量明显低于正常对照组（P〈0.01）;地塞米松干预组脾脏指数明显高于正常对照组和哮喘模型组（P〈0.01）,肾上腺指数、ACTH、BGP含量明显低于正常对照组和哮喘模型组（P〈0.05,P〈0.01）,CORT和CRH含量明显低于正常对照组（P〈0.05,P〈0.01）。结论：地塞米松干预对哮喘模型大鼠HPA轴具有很强的抑制作用,干预的不同阶段对HPA轴相关指标的抑制作用不同,并均抑制骨代谢。     

吗啡依赖与阿片受体和去甲肾上腺素能神经的适应

吸毒是当今全球性公害。我国2001年登记在册的海洛因依赖者有60.1万，目前吸毒人员仍呈增长的趋势。戒毒治疗是减少需求，减少伤害的有效手段[1，2]，对于海洛因依赖来讲，其核心问题是为什么依赖者由简单的用药发展到强迫性的用药行为？为什么戒断后又很容易回到原有的强迫性用药状态？并随着停药时间的延长，病人用药后的快感逐渐减轻的同时对药物的渴求可以保留或与日俱增。在导致依赖的起初阶段，药物引起的奖赏效应是不断用药的主要动机，而显形性特征，如持续的心理渴求和戒断后复吸行为，涉及到依赖的长程适应[3，4]。海洛因身体依赖…     

己烯雌酚对生殖系统的影响及机制的研究进展

环境雌激素是影响人类和动物健康的重要因素。己烯雌酚是酚类环境的一种雌激素,对雌性和雄性动物的生殖系统有影响。己烯雌酚可能通过雌激素受体、下丘脑-垂体-性腺轴、氧化机制和基因水平变化等对生殖系统产生影响,本文综述了己烯雌酚对生殖系统的影响及机制。     

海络因成瘾对下丘脑神经内分泌激素系统的影响

为探索海洛因依赖对人体下丘脑神经内分泌系统影响,本实验应用放射免疫法,检测了７０名海洛因依赖者脱瘤治疗前二三轴变化即下丘脑－垂体－肾上腺轴（ＰＡ）、下丘脑０垂体０甲状腺轴（ＨＰＴ）、下丘脑－垂体性腺轴（ＨＰＡＡ）共１２ 种内分泌激素水平的变化,并与６２例健康者作对照。结果显示,ＨＰＡ活性增强,ＨＰＴ、ＨＰＡＡ激素水平下降,其原因是与阿片类毒吕抑制海洛因依赖者内生阿片类物质生成和下丘脑神经元兴奋,导     

长期应用吗啡对雌性大鼠性腺轴功能的影响

目的探讨长期应用吗啡的雌性大鼠,当动情周期发生改变后,其下丘脑-垂体-卵巢轴功能的变化。方法选取30只成年雌性大鼠,采用剂量递增法皮下注射盐酸吗啡,定期进行阴道细胞学观察直至大鼠动情周期紊乱。放射免疫分析测定血清卵泡刺激素(FSH)、黄体生成素(LH)、雌二醇(E2)、孕酮(P),免疫组织化学测下丘脑、垂体、卵巢和子宫雌激素受体(ER)的表达。结果①维持吗啡用药7周时,60%(18/30)大鼠发生动情周期紊乱,用药10周,76.7%(23/30)动情周期被抑制;②长期应用吗啡,造成动情周期紊乱时,FSH、LH、E2、P基础分泌较对照组均显著降低(P<0.05,P<0.05,P<0.01,P<0.05);若长期应用吗啡后未出现动情周期紊乱,各激素水平较对照组有下降趋势;③长期应用吗啡后,无论大鼠动情周期是否被抑制,非动情期及动情期大鼠性腺轴各组织中ER平均吸光度(A)值均显著降低(P<0.01,P<0.001)。结论长期使用吗啡对下丘脑-垂体-卵巢轴有不同程度的损伤。     

海洛因和吗啡对猴的致依赖性比较

本文用吗啡依赖猴作对比,对恒河猴海洛因依赖形成的时间、累计剂量、催促实验戒断反应的量 -效、时 -效变化及自然戒断反应出现的时 -效关系等进行了研究。结果表明 :海洛因sc恒河猴,起始剂量为2.5mg·kg-1 ,tid ,每2d递增1.25mg·kg-1,日剂量达11.25mg·kg-1 后,改为每日递增1.25mg·kg-1,日剂量达到20mg·kg-1 时,维持该剂量到用药时间为3mon。给药d5,当海洛因累计剂量为17.5mg·kg-1 时,催促实验中,猴出现明显的戒断症状,以后随给药剂量的增加,戒断反应呈显著的量 -效、时 -效变化,反应强度在给药头10d内增加最快,以后呈缓慢上升的趋势。注射满3mon,突然停药,可出现明显的戒断症状,其时 -效关系与吗啡组基本一致。与吗啡组相比,在依赖形成初期,海洛因具有形成依赖时间短,用药量少,戒断反应程度严重,戒断症状稍有不同,有兴奋表现等特点。海洛因组Emax=100分,ED50 =20.9mg·kg-1;吗啡组Emax=104.2分,ED50 =80.7mg·kg-1,二者的等效剂量比为1∶3.9。自然戒断实验中,二组均达最大反应强度,且戒断反应程度基本相近。     

Asymmetrical effects of morphine and naloxone on reward mechanisms

Rats with bilaterally implanted lateral hypothalamic electrodes were tested daily for self-stimulation to each side of the brain, and rotation (circling behavior) was recorded concomitantly. All rats rotated in a preferred direction regardless of the side of the brain stimulated and all rats had asymmetries in self-stimulation sensitivity related to the direction of rotation. Morphine increased rotation and lowered self-stimulation thresholds at low doses (e.g., 2.5 mg/kg) and decreased rotation and raised self-stimulation thresholds at high doses (e.g., 20.0 mg/kg). The changes in self-stimulation thresholds preferentially occurred on opposite sides of the brain, i.e., the low-dose decrease in thresholds was greater in the normally less sensitive side of the brain whereas the high-dose increase in thresholds was greater in the normally more sensitive side of the brain. Naloxone produced no changes in rates of rotation but did elicit small changes in self-stimulation that varied with the side of the brain, i.e., dose-related decreases in thresholds occurred in the normally more sensitive side of the brain whereas dose-related increases in thresholds occurred in the normally less sensitive side of the brain. Subsequently rats were tested in a choice procedure providing concurrent access to rewarding stimulation of either side of the brain; currents were titrated such that, under baseline conditions, rats continually alternated between self-stimulating one side of the brain or the other. Morphine induced a preference for the less sensitive side of the brain that was comparable in magnitude at all doses and independent of its biphasic effects on rates of responding. Naloxone induced a dose-related preference for the more sensitive side of the brain while not altering rates of responding. Naloxone (1.0 mg/kg) also completely antagonized the effects of all doses of morphine. The results are discussed in terms of lateralized actions mediating the discriminable effects of reinforcing drugs.     

Are cholinergic mechanisms involved in morphine effects on motility?

Summary Experiments were performed to study the relevance of cholinergic mechanisms in morphine-induced effects on striatal dopamine metabolism and on motility. In rats, atropine slightly decreased the striatal homovanillic acid (HVA) concentration, but affected neither the morphine-induced rise of HVA concentration nor the catalepsy after morphine. In mice, even high doses of atropine induced only a moderate locomotor activity, compared with that observed after morphine application. Furthermore, the combination of morphine and atropine on locomotor activity seemed to be supra-additive. Although physostigmine antagonized the morphine-induced locomotor activity, the results suggest that primary effects of morphine on cholinergic mechanisms in brain are of minor importance in inducing an increase of striatal dopamine turnover and effects on motility of rats and mice.     

The effects of prenatal morphine on the responsiveness to morphine and amphetamine

The effects of morphine administered to pregnant Sprague-Dawley rats on the schedule-controlled behavior of the offspring were examined. It was observed that both male and female adult rats exposed prenatally to morphine were tolerant to the disruptive effects of morphine on fixed-interval responding compared to age-matched controls. These morphine-treated rats, however, were neither tolerant nor supersensitive to the disruptive effects of the catecholaminergic agonist, amphetamine, and did not exhibit any alteration in their steady state levels of central monoamines. These observations are discussed in relation to the effects of prenatal morphine exposure on unconditioned behaviors.     

Biphasic effects of morphine on cardiovascular system of the cat

Morphine has been reported to both lower blood pressure (BP) and cause excitation in some species. These are seemingly contradictory effects. In this series of experiments, the actions of morphine on BP, heart rate (HR) and pupillary diameter were re-examined in sedated, paralyzed cats under 2 ranges of dosage and 3 types of sedative. Small doses (1--2 mg/kg) lowered BP and HR while larger doses (8--12 mg/kg) increased both BP and HR. The effect of morphine on pupillary diameter, however, was not biphasic in that increasing doses proportionally increased pupillary diameter. In adrenalectomized cats smaller doses of morphine decreased, but larger doses no longer increased, BP and HR as it has in the non-adrenalectomized animals. Morphine also no longer produced mydriasis in the adrenalectomized cats. The results suggest that, in the cat, morphine can have a biphasic effect and that the adrenals may play a role in the excitatory phase.     

The influence of p-chlorophenylalanine on different morphine effects

p-Chlorophenylalanine (p-CPA) reduces brain 5-hydroxytryptamine (5-HT) without altering the dopamine and norepinephrine content. Morphine does not influence the 5-HT level, but partly reverses the depletion of 5-HT by p-CPA. Morphine analgesia and toxicity are not affected by p-CPA treatment. p-CPA also has no effect on acute morphine hypothermia, but after chronic treatment of 5-HT-deficient mice the dose--response curve is no longer parallel, which suggests that another mode of morphine hypothermia occurs. p-CPA diminishes morphine-induced running after acute as well as after chronic morphine administration. p-CPA treatment reduces the sensitivity to the naloxone-precipitated withdrawal reaction, but does not affect the development of physical dependence.     

Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray

The effects of the mu-opioid receptor agonists buprenorphine and morphine on immune and neuroendocrine functions through acute action in the rat mesencephalon periaqueductal gray (PAG) were evaluated. Buprenorphine is an analgesic recently approved for the treatment of drug dependency. In this study, it was shown that injection of an equianalgesic dose of buprenorphine (related to morphine) into the ventral-caudal PAG did not alter splenic NK cell, T cell, and macrophage functions, whereas morphine significantly (p<0.001) suppressed splenic NK cell cytotoxic activity (14-50% reduction), splenic and thymic T cell proliferation to concanavalin A (Con A, 43-76% reduction), antiTCR (T cell receptor) (85% reduction) and IL-2 (36-48% reduction), and macrophage functions including nitric oxide (36-41% reduction) and TNF-alpha production (26%), and phagocytosis of Candida albicans (39%). In addition, buprenorphine was associated with significant (p<0.0001) reductions in adrenocorticotropic hormone (ACTH) and corticosterone (CSO) plasma levels, without altering norepinephrine (NE) and serotonin splenic dialysate levels. In contrast, morphine significantly (p<0.0001) increased glucocorticoid and catecholamine levels in plasma and spleen dialysates, respectively. These results indicated that buprenorphine did not activate either the hypothalamic-pituitary-adrenal (HPA) axis with glucocorticoid release, or the sympathetic nerve (SNS) activity with bioamine production, and was not associated with immunosuppression. The lack of effects of buprenorphine on neuroendocrine systems may be related to its partial agonist properties, the absence of effects on immune system function, and may be associated with the reduction in craving observed in addictive disorders.     

The effects of thyrotropin-releasing hormone on the central nervous system responses to chronic morphine administration

The effects of thyrotropin-releasing hormone (TRH) on abrupt and naloxone-precipitated abstinece symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by SC implantation of morphine pellets. Intracerebral (IC) administration of TRH inhibited the hypothermic response observed during abrupt (removal of morphine pellets) and naloxone (0.1 mg/kg SC) precipitated withdrawal. IC injection of TRH also inhibited the naloxoneprecipitated withdrawal jumping response as evidenced by increases in the dose of naloxone required to elicit the response. The effects of TRH on the development of morphine dependence were also investigated. A single SC injection of TRH (4–16 mg/kg) did not modify development of morphine dependence. Administration of TRH prior to and during morphine pellet implantation inhibited the development of dependence as evidenced by inhibition in the development of abrupt and naloxone-induced withdrawal hypothermia. Even though the hypothermic response was blocked, multiple SC administration of TRH failed to modify naloxone-induced stereotyped jumping response. These studies indicate that TRH administration can modify central nervous system responses to chronic morphine treatment and that separate sites may initiate withdrawal jumping behavior and affect temperature regulation during abrupt and antagonist-induced abstinence.This work was presented in part at the International Narcotic Research Conference, North Falmouth, Massachusetts, June 10–15, 1979     

The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence.

The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg x kg(-1). In the second 3 days the initial dose was doubled (20 mg x kg(-1)) and in the last 3 days the dose of M was raised to 40 mg x kg(-1). On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg x kg(-1)M, 2 mg x kg(-1) 4-AP 105 min after 80 mg x kg(-1) M, and 80 mg x kg(-1) M 105 min before 2 mg x kg(-1) 4-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg x kg(-1) 4-AP 105 min prior to M administration, which was increased every 3 days (10 mg x kg(-1), 20 mg x kg(-1), 40 mg x kg(-1)). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg x kg(-1) 4-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg x kg(-1) M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg x kg(-1) 4-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg x kg(-1) NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named 'total number of others'. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.     

The effects of gepirone on neuroendocrine function and temperature in humans

The effects of the selective 5-HT_1A receptor agonist gepirone (10 and 20 mg orally) on neuroendocrine function and temperature were assessed using a single-blind cross-over design in 12 healthy male volunteers. Gepirone significantly increased plasma levels of ACTH,-endorphin, cortisol, prolactin and growth hormone. Following gepirone there was a significant decrease in body temperature and moderate increases in subjective reports of light-headedness, nausea and drowsiness. Our results are consistent with studies in rodents suggesting that 5-HT_1A receptor agonists increase ACTH and prolactin secretion and decrease body temperature. Further investigations are needed to determine if the neuroendocrine and temperature effects of gepirone in humans are mediated by 5-HT_1A receptors.