抑郁症患者血浆孤啡肽含量研究

目的为探讨抑郁症的可能病因,对抑郁症患者血浆孤啡肽(OFQ)含量进行了对照研究。方法抽取29例抑郁症患者和24例正常人的静脉血,用放射免疫(RIA)的方法分别测其血浆中OFQ含量,比较抑郁症患者和正常人血浆OFQ含量有无差异,抑郁症患者OFQ含量与汉密顿抑郁量表(HAMD)评分的相关性,及抑郁症患者血浆OFQ含量的影响因素。结果与正常人比较,抑郁症组OFQ含量明显升高(t=8．70,P＜0．0001)；OFQ含量与HAMD评分呈正相关(r=0．63,P＜0．01)；OFQ含量主要与抑郁情绪、夸大、失眠、自卑感、自杀、强迫症状、教育水平、关注身体健康等因素相关,而年龄、性别、职业、病程、曾用药等其他因素与OFQ含量无明显相关。结论通过测量血浆OFQ含量可作为抑郁症诊断的参考指标。     

鞘内注射孤啡肽对吗啡耐受形成及吗啡耐受大鼠抗伤害感受作用的影响

目的:观察孤啡肽(OFQ)对大鼠吗啡耐受的形成是否具有延缓作用,以及OFQ与吗啡间是否存在交叉耐受性.方法:本实验运用热辐射甩尾测痛模型,采用鞘内同时注射不同剂量的OFQ与吗啡,观察其对急、慢性吗啡耐受形成的影响;并观察OFQ对吗啡耐受大鼠及吗啡对OFQ耐受大鼠的抗伤害性感受作用.结果:鞘内注射OFQ可延缓慢性吗啡耐受的形成,而对急性吗啡耐受的形成几乎无影响;OFQ与吗啡间无交叉耐受性.结论:OFQ延缓慢性吗啡耐受形成的作用可能与其通过受体后信号转导途径影响G蛋白-AC-cAMP系统有关,也可能与其抑制伏隔核多巴胺的释放有关;OFQ与吗啡耐受形成的机制可能不同,OFQ可能通过其特异性受体发挥脊髓抗伤害性感受作用.     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity,stress, anxiety,mood, and drug dependence

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.     

孤啡肽逆转人白血病K562/ADM细胞耐药性的研究

目的 探讨孤啡肽对人白血病K562/ADM细胞对阿霉素耐药性的逆转作用.方法 测定孤啡肽的细胞毒性及其对K562/ADM细胞药物敏感性的影响,计算耐药逆转倍数.瑞士染色观察药物作用后K562/ADM细胞形态的改变;流式细胞仪检测阿霉素单用或与孤啡肽联用K562/ADM细胞凋亡百分率;DNA琼脂糖凝胶电泳观察孤啡肽与阿霉素联用后K562/ADM细胞内DNA的损伤程度.结果 非细胞毒性剂量的孤啡肽(10-7mol/L)作用于K562/ADM细胞时,对阿霉素耐药起到了部分逆转作用,使K562/ADM细胞的IC50由原来的(46.99±0.25)μg/ml降低至(23.11±0.29)μg/ml,其逆转倍数为2.03倍;孤啡肽(10-7mol/L)和阿霉素(20μg/ml)联合处理K562/ADM细胞48h,K562/ADM细胞呈典型的凋亡形态改变;细胞的凋亡率达到(18.73±3.90)%,明显高于两种药物在相同条件下单独作用的效果,P＜0.01;结论 孤啡肽能诱导K562/ADM细胞凋亡,从而能逆转K562/ADM细胞的耐药性,提高阿霉素的敏感性.     

山莨菪碱对脑外伤后急性肾损害大鼠血浆、肾组织匀浆孤啡肽含量变化的影响

目的探讨山莨菪碱对颅脑损伤后发生急性肾损害时血浆、肾组织中孤啡肽含量变化的影响及治疗作用。方法通过RIA方法测定大鼠脑损伤以及山莨菪碱治疗后血浆及肾组织匀浆孤啡肽含量的变化。结果脑损伤组血浆、肾组织匀浆中孤啡肽含量明显高于对照组(P<0.01),山莨菪碱治疗组血浆、肾组织匀浆中孤啡肽含量明显低于脑损伤组(P<0.01)。结论血浆及肾组织匀浆中孤啡肽含量增高可能是参与脑损伤后的急性肾损伤过程中的一个重要因素;山莨菪碱通过降低血浆及肾组织孤啡肽含量,而发挥对脑损伤后急性肾损伤一定的保护作用。     

Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys

Rationale Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.Objectives The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S⁺) and a 1-s cue light (CS⁺) or for water in the presence of anise odour (S^–) and 1-s white noise (CS^–), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.Results Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 g or 1.0 g N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 g of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0–2.0 g per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S⁺/CS⁺ condition, whereas lever pressing under S^–/CS^– was not altered.Conclusions The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.     

Central administration of nociceptin/orphanin FQ blocks the acquisition of conditioned place preference to morphine and cocaine, but not conditioned place aversion to naloxone in mice

Rationale Previous studies have suggested that nociceptin (known also as orphanin FQ) suppresses the rewarding potential of morphine and alcohol in the rat. However, little is known of the effect of nociceptin on the rewarding properties of these and other drugs in the mouse.Objective To determine the effect of nociceptin on opiate or psychostimulant-induced conditioned place preference, or naloxone-induced conditioned place aversion in mice.Methods C57BL6 mice were implanted with chronically indwelling intracranial cannulae targeted at the lateral cerebroventricle through which nociceptin (0.06, 0.6, or 6 nmol) could be administered. Animals were conditioned in an unbiased balanced paradigm to study the effect of nociceptin administration alone, or the effect of nociceptin on the acquisition of place conditioning to morphine, cocaine, or naloxone (all 7.6 mg/kg subcutaneous).Results Administration of 0.06 nmol nociceptin alone stimulated locomotion during conditioning sessions, but had no hedonic effects. In contrast, administration of 6 nmol nociceptin alone markedly reduced basal locomotion during the conditioning sessions and induced a mild place aversion. Both morphine and cocaine induced robust place preferences, the acquisition of which was dose dependently suppressed by administration of nociceptin at doses of 0.6 nmol and above. Conditioning with naloxone produced a robust place aversion that was only weakly blocked by the maximum dose of nociceptin tested.Conclusion Nociceptin blocks the rewarding properties of drugs in both narcotic analgesic and psychostimulant classes in the mouse. In contrast, nociceptin has only a minor effect on the negative affective state experienced following naloxone administration.     

The rostral ventromedial medulla mediates the facilitatory effect of microinjected orphanin FQ in the periaqueductal gray on spinal nociceptive transmission in rats

Single unit extracellular recordings from spinal dorsal horn neurons were obtained with glass micropipettes in pentobarbital-anesthetized rats. A total of 50 wide dynamic range (WDR) neurons were studied in 25 rats. Microinjection of orphanin FQ (OFQ, 0.1 microg/0.1 microl) (a potent endogenous ligand of the opioid receptor-like receptor (ORL-1)) into the ipsilateral ventrolateral parts of periaqueductal gray (vlPAG) significantly increased C-response and post-discharge activity in most of the WDR neurons. Pre-microinjection of lidocaine (4%) into the nucleus raphe magnus (NRM) (0.5 microl), ipsilateral nucleus reticularis gigantocellularis (NGC) (0.6 microl), or nucleus gigantocellularis pars alpha (NGCalpha) and nucleus reticularis paragigantocellularis lateralis (NPGL) (0.5 microl) markedly reduced intra-vlPAG microinjection of OFQ-induced facilitatory effects on nociceptive responses of WDR neurons. Furthermore, if the NRM and ipsilateral NGC were simultaneously pre-microinjected with lidocaine, the intra-vlPAG microinjection of OFQ-induced facilitation on nociceptive responses of WDR neurons was eliminated. Also, a similar effect was observed when all the NRM, ipsilateral NGC, NGCalpha and NPGL were blocked with lidocaine. No significant effect on nociceptive responses of WDR neurons per se was found after blocking the NRM, ipsilateral NGC, NGCalpha/NPGL, or all the NRM, ipsilateral NGC, and NGCalpha/NPGL with lidocaine. These results indicate that (1) the facilitatory effect evoked by microinjection of OFQ into the vlPAG on nociceptive responses of WDR neurons in the spinal dorsal horn is primarily mediated by the NRM and ipsilateral NGC; (2) the NRM, ipsilateral NGC, and NGCalpha/NPGL do not mediate tonic descending inhibition of the spinal dorsal horn neurons.     

Distribution of ORL-1 receptor binding and receptor-activated G-proteins in rat forebrain and their experimental localization in anterior cingulate cortex

Opioid receptor-like (ORL-1) receptors and ORL-1-activated G-proteins are found in high levels in the forebrain, particularly cingulate cortex, an area involved in processing of nociceptive stimuli. [(3)H]nociceptin/orphanin FQ (N/OFQ) and N/OFQ-stimulated [(35)S]GTPgammaS autoradiography in rat brain were used to localize ORL-1 receptors and activated G-proteins, respectively. N/OFQ binding and activated G-proteins were highest in anterior cingulate, agranular insula, piriform, perirhinal and entorhinal cortices; midline and intralaminar thalamic nuclei; and subnuclei of the amygdala and hippocampus. In anterior cingulate area 24, [(3)H]N/OFQ and N/OFQ-stimulated [(35)S]GTPgammaS binding were highest in layers V and VI. The cellular localization of ORL-1 receptors and activated G-proteins in area 24 was examined using two strategies: ibotenic acid injection into the cortex or undercut lesions to remove afferent axons, followed by autoradiography. Ibotenic acid lesions that destroyed neurons in the anterior cingulate cortex decreased [(3)H]N/OFQ binding by 75-80% and reduced N/OFQ-stimulated [(35)S]GTPgammaS binding to basal levels seen in the absence of agonist. Deafferentation lesions increased [(3)H]N/OFQ binding by 40-50%, with no significant change in N/OFQ-stimulated [(35)S]GTPgammaS binding. These data demonstrate that ORL-1 receptors in layer V of anterior cingulate cortex are located on somatodendritic elements and that deafferentation increases ORL-1 receptor binding.