纳洛酮对家兔迷走-加压反应的影响

本文观察了刺激家兔颈迷走神经中枢端所引起的加压反应(迷走-加压反应)和侧脑室内注射纳洛酮对家兔迷走-加压反应的影响,结果表明:刺激家兔颈迷走神经中枢端而引起的加压反应可为侧脑室注射纳洛酮后而抑制,这提示内源性阿片样物质参与家兔的迷走-加压反应过程。     

家兔杏仁核内的5-羟色胺和内源性吗啡样物质在电针镇痛和吗啡镇痛中起重要作用

本工作的目的是要确定杏仁核内的吗啡样物质(内啡素)和5-羟色胺(5-HT)是否参与电针镇痛和吗啡镇痛。经慢性埋植套管向家兔杏仁核内微量注射阿片受体阻断剂纳洛酮,或5-HT受体阻断剂肉桂硫胺,可使电针的镇痛效果显著减弱,尤以注入中央杏仁核作用最为显著,双侧注射效果大于单侧,注入核外则无效。杏仁核内注入5-HT 的前体5-HTP,或脑啡肽降解酶抑制剂 D-苯丙氨酸可使电针镇痛显著加强。上述措施凡是加强或对抗电针镇痛的,也能加强或对抗吗啡镇痛。以上结果表明,电针刺激或注射吗啡可能在杏仁核内引起5-HT 和内啡素(很可能是脑啡肽)的释放,而发挥镇痛效应。     

脑室注射P物质对大鼠血压、心率及交感传出活动的影响

给乌拉坦麻醉六鼠侧脑室注射P物质(SP)10μg,引起动脉血压、心率和内脏交感神经放电增加。同样剂量的SP静脉注射后却引起血压降低。阿托品预处理不影响SP的开心率作用。预先脑室注射0.25,4,64μg阿片受体拮抗剂纳洛酮,对SP的升压效应有剂量依赖式对抗作用。以上说明脑室注射SP 引起的血压升高是交感神经活动增强,导致心率加快及外周血管紧张性增加的结果,并提示SP的中枢升压效应可能与脑内释放内源性阿片样物质有关。     

纳洛酮和内毒素性休克

自从1973年发现特异性阿片受体以后,又相继在哺乳动物脑组织内发现和分离出5肽的脑啡肽和31肽的内啡肽。近年来,又相继在脑和外周组织中发现其它内源性阿片样物质。虽然对内源性阿片样物质的研究主要集中在痛的调节方面,但近年来已有越来越多的研究揭示内源性阿片样物质可能是一种重要的神经调质(neuromodulator),它在调节神经、精神、内分泌活动、癫痫、学习记忆、性行为、睡眠觉醒以及呼吸和心血管等生理病理活动中有重要作用。纳洛酮作为阿片受体的特异性拮抗剂,在研究内源性阿片样物质作用中是不可缺少的工具。     

家兔伏核—杏仁核神经通路在吗啡镇痛中的作用

用辐射热照射家兔鼻嘴侧部皮肤,测量其躲避反应潜伏期作为痛反应阈,简称痛阈。通过预先埋植的慢性套管向伏核或杏仁核内进行注射,结果表明:(1)在家兔的伏核内微量注射吗啡可产生镇痛作用,该作用可被杏仁核内注射纳洛酮所削弱,并有量效依从关系;在杏仁核内注射甲啡肽抗血清(ME AS)或β-內啡肽抗血清(β-EP AS)亦可削弱上述镇痛作用;(2)在杏仁核内微量注射吗啡可产生镇痛作用,此作用不能被伏核内注射纳洛酮所阻断;(3)在伏核内注射吗啡所产生的镇痛作用可被同一部位注射γ-氨基丁酸(GAEA)受体阻断剂氯甲基荷包牡丹碱所增强,被 GABA 受体激动剂异鹅羔胺所削弱。上述结果提示:在家兔脑内从伏核到杏仁核可能存在一条与镇痛有关的神经通路,伏核内的阿片样物质及杏仁核内的甲啡肽,β-内啡肽可能参与镇痛信息的传递,而伏核内的 GABA 可能有对抗吗啡镇痛的作用。     

脑室注射纳洛酮对大鼠迷走-加压反应的影响

本文研究了太鼠的迷走-加压反应和脑室注射纳洛酮对大鼠迷走-加压反应的影响。其结果为:1.刺激大鼠迷走神经向中端,可出现迷走-加压反应;2.脑室注射纳洛酮15—20分钟左右,大鼠迷走-加压反应显著抑制;50分钟左右抑制效应解除,迷走-加压反应开始复现。以上事实提示:内源性阿片样物质参与大鼠的迷走-加压反应过程,对迷走-加压反应可能起加强作用。     

抗阿片生物活性物质

大量的工作已经证明,内源性阿片样物质在中枢神经系统中广泛分布,并具有十分复杂的生理功能。随着这方面工作深入,对于脑内是否存在其对抗性物质已引起人们注意。已经从脑内分离提取得到了某些具有对抗阿片活性的未知物质,同时也发现了某些已知的神经化学物质,特别是神经肽,也可不同程度地调节阿片样物质的活性。     

抗阿片生物活性物质

大量的工作已经证明,内源性阿片样物质在中枢神经系统中广泛分布,并具有十分复杂的生理功能.随着这方面工作深入,对于脑内是否存在其对抗性物质已引起人们注意.已经从脑内分离提取得到了某些具有对抗阿片活性的未知物质;同时也发现了某些已知的神经化学物质,特别是神经肽,也可不同程度地调节阿片样物质的活性.     

躯体传入冲动对刺激兔下丘脑诱发期前收缩的抑制作用

1.以低频、低强度方波刺激腓深神经或正中神经可以抑制由刺激下丘脑引起的期前收缩。若电刺激过强或刺激腓浅、挠浅、前臂外侧皮神经则无此作用。2.刺激躯体神经对期前收缩的抑制作用与迷走神经及心室后负荷无密切关系,很可能是通过抑制心交感中枢紧张性来实现的。3.刺激下丘脑诱发的期前收缩可为中央灰质内微量注入吗啡所抑制,而为微量注入纳洛酮所增多,微量注入纳洛酮并可阻断躯体传入冲动对期前收缩的抑制作用。表明此种抑制作用有脑内鸦片受体与吗啡样物质参与。     

纳洛酮翻转刺激大鼠下丘脑弓状核对中缝背核单位活动的影响

实验在麻醉或制动的大鼠上进行。用玻璃微电极记录中缝背核单位活动及其对刺激弓状核的反应,并观察注射纳洛酮的作用。主要结果如下:(1)电刺激弓状核能明显影响中缝背核单位的放电活动,主要表现为抑制;(2)注射纳洛酮能翻转刺激弓状核对中缝背核单位放电的影响;(3)注射纳洛酮使中缝背核单位的自发放电频率显著增加。上述结果提示:刺激弓状核对中缝背核单位放电的影响,可能是通过释放内源性阿片样物质(β-内啡肽)而引起的。     

Stress-induced decrease of 3-methoxytyramine in the nucleus accumbens of the mouse is prevented by naltrexone pretreatment

Pretreatment with naltrexone (2.5 and 5 mg/kg) prevented the decrease of 3-methoxytyramine (3-MT)/dopamine (DA) ratio induced by 2 h immobilization stress in the nucleus accumbens (NAS) of the mouse while it did not affect the stress-induced decrease of 3-MT/DA ratio in caudatus putamen (CP). Naltrexone also produced a slight antagonism of homovanillic acid (HVA)/DA ratio increase produced by stress in the frontal cortex (FC). These results point to an involvement of endogenous opioids in the effects of stress on DA metabolism in the mesolimbic system of the mouse.     

Suppression of serum prolactin by naloxone but not anti-β-endorphin antiserum in stressed and unstressed rats

The role of endogenous opioids in the regulation of tonic and stress-induced prolactin secretion was studied in male rats. Animals with chronically indwelling intra-atrial catheters were used and served as their own controls. Intravenous injection of a potent rabbit anti-β-endorphin antiserum produced no change in either baseline serum prolactin or in the rise induced by swimming for 15 minutes at 20 C. Naloxone, 0.5 mg/kg intravenously, produced a small but statistically significant lowering of baseline serum prolactin levels, as well as a mild blunting of the stress-induced serum prolactin rise. The failure of anti- - endorphin antiserum to affect serum prolactin may be explained either by failure of the antiserum to gain access to hypothalamic prolactin regulating loci, or to lack of involvement of β-endorphin in the control of serum prolactin. The suppression of prolactin secretion seen with naloxone indicates that endogeneous opioids are involved in prolactin regulation, though the relatively small magnitude of the changes observed suggests that their role under physiological conditions may be a minor one.     

Role of alimentary hyperglycemia in the pathogenesis of several disorders of lipid metabolism]

Alimentary hyperglycemia in rabbits was found to be accompanied by increase in cholesterol level, as well as in the amount of triglycerides in the blood sera. Progressive increase in the serum concentration of pre-beta lipoproteids (serving as endogenous tryglyceride carrier) has also been demonstrated. A short-term feeding with cholesterol against the background of hyperglycemia in rabbits appeared to result in early marked atherosclerotic changes, as compared to those in control group of normoglycemic animals.     

Cholesterol catabolism in the rabbit in fasted and fed states.

Urinary and fecal endogenous steroid excretion of fed or fasted New Zealand white rabbits was determined by the isotopic steady state method after subcutaneous implantation of radioactive cholesterol. While plasma cholesterol was increasing during a 9-day fast, fecal steroid excretion decreased to 10% of the excretion rates in the fed state. Refeeding the fasted rabbits led to a decrease in plasma cholesterol and an increase in fecal endogenous steroid excretion. Urinary steroid excretion, which represented 18% of total endogenous steroid excretion for fed animals, decreased during fasting and increased during refeeding, but these changes were relatively small. The small intestine, cecum, and colon of fed or fasted rabbits had similar endogenous steroid was acidic steroid. During attempts to alter the circulating bile acid concentration by supplying deoxycholate (200 mg/day) to fed rabbits or cholestyramine (2 g/day) to fasted rabbits, plasma cholesterol concentration did not change to the same extent as during fasting or refeeding, respectively. The decreased cholesterol catabolism and the hypercholesterolemia that are seen in the fasting rabbit may result from decreased clearance of plasma cholesterol.     

Stress induced changes in testis function

The mechanism through which chronic stress inhibits the hypothalamic-pituitary-testicular axis has been investigated. Chronic restraint stress decreases testosterone secretion, an effect that is associated with a decrease in plasma gonadotropin levels. In chronically stressed rats there was a decrease in hypothalamic luteinizing hormone-releasing hormone (LHRH) content and the response on plasma gonadotropins to LHRH administration was enhanced. Thus the inhibitory effect of chronic stress on plasma LH and FSH levels seems not to be due to a reduction in pituitary responsiveness to LHRH, but rather to a modification in LHRH secretion. It has been suggested that beta-endorphin might interfere with hypothalamic LHRH secretion during stress. Chronic immobilization did not modify hypothalamic beta-endorphin, while an increase in pituitary beta-endorphin secretion was observed. Since we cannot exclude that changes in beta-endorphin secreted by the pituitary or other opioids may play some role in the stress-induced decrease in LHRH secretion, the effect of naltrexone administration on plasma gonadotropin was studied in chronically stressed rats. Naltrexone treatment did not modify the decrease in plasma concentrations of LH or FSH. These findings suggest that the inhibitory effect of restraint on the testicular axis is exerted at hypothalamic level by some mechanism other than opioids.     

Endocrine actions of opioids

The widespread occurrence of opioid peptides and their receptors in brain and periphery correlates with a variety of actions elicited by opioid agonists and antagonists on hormone secretion. Opioid actions on pituitary and pancreatic peptides are summarized in Table 1. In rats opioids stimulate ACTH and corticosterone secretion while an inhibition of ACTH and cortisol levels was observed in man. In both species, naloxone, an opiate antagonist, stimulates the release of ACTH suggesting a tonic suppression by endogenous opioids. In rats, a different stimulatory pathway must be assumed through which opiates can stimulate secretion of ACTH. Both types of action are probably mediated within the hypothalamus. LH is decreased by opioid agonists in many adult species while opiate antagonists elicit stimulatory effects, both apparently by modulating LHRH release. A tonic, and in females, a cyclic opioid control appears to participate in the regulation of gonadotropin secretion. Exogenous opiates potently stimulate PRL and GH secretion in many species. Opiate antagonists did not affect PRL or GH levels indicating absence of opioid control under basal conditions, while a decrease of both hormones by antagonists was seen after stimulation in particular situations. In rats, opiate antagonists decreased basal and stress-induced secretion of PRL. Data regarding TSH are quite contradictory. Both inhibitory and stimulatory effects have been described. Oxytocin and vasopressin release were inhibited by opioids at the posterior pituitary level. There is good evidence for an opioid inhibition of suckling-induced oxytocin release. Opioids also seem to play a role in the regulation of vasopressin under some conditions of water balance. The pancreatic hormones insulin and glucagon are elevated by opioids apparently by an action at the islet cells. Somatostatin, on the contrary, was inhibited. An effect of naloxone on pancreatic hormone release was observed after meals which contain opiate active substance. Whether opioids play a physiologic role in glucose homeostasis remains to be elucidated.     

Hypoxia does not increase CSF or plasma beta-endorphin activity

The ability of moderate (30-50 Torr arterial PO2) and severe (less than 30 Torr arterial PO2) hypoxia to generate endogenous opioids that modulate ventilation was studied in unanesthetized goats. Ventilation and its components, arterial blood gas tensions and pH, and plasma and cerebrospinal fluid (CSF) beta-endorphin activity were measured before and after 4 h of sustained moderate or severe hypoxia. Ventilation, as expected, increased with hypoxia. There were no significant changes in either plasma or CSF beta-endorphin activity after sustained hypoxia. To rule out elaboration of endogenous opioids other than beta-endorphin after hypoxia, naloxone or saline was administered to five of the seven goats exposed to 4 h of severe hypoxia, and their ventilatory responses were compared for 30 additional min of hypoxic breathing. No significant differences in ventilation occurred in the two treatment groups during this time period. We conclude that, unlike increases in airway resistance, moderate and severe hypoxia do not cause the elaboration of endogenous opioids that modify respiratory output in unanesthetized adult goats. The apparent ability of hypoxia to cause elaboration of endogenous opioids in the neonate may represent a maturational phenomenon.     

Effects of naloxone on pavlovian conditioning of eyeblink and heart rate responses in rabbits

Albino rabbits were subjected to aversive Pavlovian conditioning and extinction of eyeblink and heart rate responses. Naloxone administration had no effect on acquisition of the eyeblink response but increased responding during extinction. Naloxone also attenuated the bradycardiac heart rate CR, suggesting that endogenous opioids may be involved in mediating this response.     

Endogenous opiates and behavior: 2014

This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).     

Effects of naloxone on breathing movements during hypercapnia in the fetal lamb

To determine whether endogenous opioids influence the fetal breathing response to CO2 we have investigated the effect of the opiate antagonist, naloxone on the incidence, rate, and amplitude of breathing movements during hypercapnia in fetal lambs in utero. In 20 experiments in six pregnant sheep (130-145 days gestation) hypercapnia was induced by giving the ewe 4-6% CO2-18% O2 in N2 to breathe for 60 min. After 30 min of hypercapnia either naloxone (13 experiments) or saline (7 experiments) was infused intravenously for the remaining 30 min. During hypercapnia breath amplitude increased from 5.8 +/- 0.5 to 9.1 +/- 1.2 mmHg (P less than 0.001), and infusion of naloxone was associated with a further significant increase to 15.7 +/- 1.2 mmHg (P less than 0.001). Naloxone had no effect on the incidence or rate of breathing movements during hypercapnia. After hypercapnia there was a significant decrease in the incidence of fetal breathing movements in the naloxone group (14.7 +/- 3.2%). Infusion of saline during hypercapnia had no effect on incidence, rate, or amplitude of fetal breathing movements. These results suggest that endogenous opioids act to suppress or limit breath amplitude during hypercapnia but do not affect rate or incidence of breathing movements.