Prolonged Receptor Blockade by Opioid Receptor Probes

Opioid receptor interactions of morphinan-type opioids derivatized at the C-6 carbon were investigated. The compounds, designed as probes for studying opioid receptors, were characterized with regard to affinity for the rat brain mu receptor by competition with tritium-labeled dihydromorphine (³H-DHM). All compounds were also screened for prolonged receptor blockade by preincubation of rat brain membranes with the compounds alone, followed by extensive washing, and incubation with ³H-DHM. The apparent dissociation profiles of congeners with prolonged blockade were further studied in the presence and absence of physiological concentrations of salts. Under conditions that completely dissociate the parent opioids, naltrexone, naloxone, and oxymorphone, the derivative l-(N-fluoresceinyl naltrexone thiosemicarbazone (6-FNX) and the opioid-steroid hybrids naloxone estrone azine (N-EH) and androstene bisoxymorphone azine (O-AD-O) showed more persistent receptor blockade than the bivalent opioid naloxonazine (NAz). Neither chemical reactivity nor a bivalent opioid structure was found to be a prerequisite for prolonged receptor blockade.     

Progressive central hypovolaemia in man—resulting in a vasovagal syncope?

Summary. Hypotensive functional haemorrhage induced by venous pooling of blood in the legs has been reported to be characterized by a vasovagal reaction. In the present study these observations were extended by determination of the hormonal profile developed during progressive central hypovolaemia and an emotionally induced vasovagal syncope. In six subjects venous pooling resulted in normotensive central hypovolaemia, in one subject hypotensive central hypovolaemia was induced, and one subject experienced an emotionally induced vasovagal syncope. During normotensive central hypovolaemia heart rate increased from 58 ± 4 to 76 ± 4 beats min^-1 (P<0·05) and cardiac output fell from 6·1 ± 0·4 to 4·1 ± 0·21 min^-1. Pulse pressure and central venous pressure decreased from 64 ± 4 to 53 ± 4 mmHg, and from 8 ± 2 to 3 ± 2 mmHg, respectively. Adrenalin and noradrenalin increased from 87 ± 10 to 120 ± 20 pg/ml and from 196 ± 33 to 370 ± 50 pg/ml, respectively. Angiotensin II increased from 13 ± 4 to 36 ± 6 pg/ml and aldosterone from 63 ± 9 to 180 ± 27 pg/ml. In hypotensive central hypovolaemia the decrease in mean arterial pressure was accompanied by a decrease in heart rate and increments in the plasma concentrations of pancreatic polypeptide, indicating increased vagal activity and β-endorphin, while plasma noradrenalin was unchanged. In emotionally induced syncope heart rate decreased to cardiac arrest for 13 s, associated with increments in the plasma concentrations of pancreatic polypeptide and β-endorphin. It is concluded (1) that normotensive functional haemorrhage in man is associated with increased sympathetic activity and (2) that the qualitatively similar observations obtained during an emotionally and a hypovolaemic-induced hypotensive episode indicate that the hypotensive functional haemorrhage is characterized by a vasovagal reaction.     

出血性中风患者血浆及脑脊液中β－内啡呔和强啡呔含量的变化

测定了１０例急性脑出血和８例急性蛛网膜下腔出血患者血浆及脑脊液（ＣＳＦ）中β－内啡呔（β－ＥＰ）和强啡呔（ＤｙｎＡ）的含量。结果脑出血组血浆和ＣＳＰ中β－ＥＰ和ＤｙｎＡ含量均显著增高；蛛网膜下腔出血组ＣＳＦ中β－ＥＰ和ＤｙｎＡ增高，血浆中仅β－ＥＰ含量增高，提示这两种内源性阿片肽参与了出血性中风的病理生理过程，并可能是加重其继发性中枢神经系统损害的因素之一。     

Emotional numbing: A possible endorphin-mediated phenomenon associated with post-traumatic stress disorders and other allied psychopathologic states

Numbeing of general responsiveness associated with post-traumatic stress disorders is postulated to represent a psychobiological response to overwhelming stress mediated by a hypersecretion of the endogenous opiate system. Evidence for the hypothesis is inferential and is based on: (1) similarities between behavioral symptoms of the numb state and the effects of opioids on animals and man; (2) the stress induced analgesia phenomenon, an endorphin mediated response leading to reduction of pain and fear; (3) Solomon's Opponent Process Theory, which offers a conceptual framework for understanding how the numb response can become the dominant psychopathologic disturbance in a chronic condition. Catastrophe theory models are introduced to describe and explain the relationship of emotional nonresponsiveness to rage and other affective states. In addition, other psychiatric states in which flat affect, apathy, and social withdrawal predominate are highlighted as phenomenologically and dynamically similar to the numb state and are posited to also be regulated by the endogenous opiate system.     

盐酸纳洛酮对颅脑手术病人血浆和脑脊液β-内啡肽的影响

目的:通过观察在颅脑手术中盐酸纳洛酮对血浆和脑脊液中β-内啡肽(β-EP)的影响,探讨盐酸纳洛酮的脑保护作用.方法:32例择期颅脑手术病人ASAⅠ～Ⅱ级,随机分为纳洛酮组(Ⅰ组)和对照组(Ⅱ组).采用放射免疫分析法检测血浆及脑脊液中β-EP的含量.结果:纳洛酮组在给药后1 h( T2期)、给药后2 h(T3期)和给药后3 h(T4期)血浆β-EP含量分别为(187.76±81.37)、(109.56±45.92)和(69.37±21.66) ng*L-1,脑脊液中含量分别为(2 169.61±416.37)、(1 369.85±433.55)和(987.62±278.19) ng*L-1,均较给药前(T1期)即开始切硬膜时低(P<0.05),纳洛酮组血浆和脑脊液中的β-EP均低于对照组同期值(P<0.05).结论:颅脑手术围术期应用纳洛酮可以使脑脊液和血浆中β-EP含量降低,从而说明应用纳洛酮可以减轻脑水肿和损伤,保护脑细胞.     

Effects of beta-endorphin and met-enkephalin on platelet activity

In the present study, beta-endorphin and met-enkephalin were tested for their antiplatelet activity in human platelet-rich plasma (PRP). Blood samples were obtained from 15 healthy subjects. The results of the study show that these two endogenous opioids (200 pg/ml final concentration) reduce platelet aggregation when it is induced by ADP at low dose (0.5 microM). It is likely due to conformational changes on the platelet membrane that cause a non-specific decreased susceptibility to platelet-aggregating agonists.     

Primary central alveolar hypoventilation in a child: early diagnosis during acute illness; trials with respiratory stimuli; studies related to endorphins

Primary central alveolar hypoventilation (PCAH) has been described in adults, children, and infants. It is usually diagnosed clinically at an advanced stage when the secondary effects of chronic hypoxia and hypercapnia become evident. We report here PCAH in its early stage in a 7-year-old child, whose disease appeared as acute respiratory failure during an acute illness. When the acute illness subsided, the salient features of PCAH remained and were studied in some detail. We also describe the child's response to respiratory stimuli, and some results related to endorphins, including his plasma endorphin levels and response to a trial of naloxone.     

阿片肽参与胆囊收缩素对下丘脑神经内分泌调控的研究

利用放射免疫分析法,观察了腹腔注射和侧脑室注射胆囊收缩素-8(CCK-8)后,大鼠垂体、脑区及脊髓内β-内啡肽(B-EP)、强啡肽A(Dyn.A)含量的变化。结果如下:①腹腔注射CCK-8(5μg/kg),垂体内β-EP含量显著增加(P<0.05)。②侧脑室注射CCK-8(2.5μg/kg;10μl),10min和20min后,垂体内β-EP含量显著升高(P<0.05);Dyn.A的含量升高极显著(P<0.01)。结果提示,内源性阿片肽可能参与CCK-8对下丘脑神经内分泌的调控活动。     

SYNTHESIS AND RADIORECEPTOR BINDING ACTIVITY OF TURKEY β-ENDORPHIN AND DEACETYLATED SALMON ENDORPHIN

Des-acetylated salmon endorphin and turkey β endorphin have been synthesized by the solid-phase method. Relative opiate activities in a radioreceptor binding assay are: human β-endorphin, 100; des-acetylated salmon endorphin, 169; turkey β-endorphin, 94. Thus, non-mammalian endorphins can show high activity in a mammalian assay system.