Dynorphin(1-13) improves survival in cats with focal cerebral ischaemia

Since the discovery of opiate receptors in the central nervous system (CNS), it has become apparent that endogenous opiate ligands are involved in CNS function. Most attention has focused on their role in modulating pain, but they have also been implicated in various physiological functions and in disease states. We are concerned with evidence that endogenous opioid peptides may also contribute to the neurological deficits arising from cerebral ischaemia. Dynorphin, which is widely distributed in the brain and pituitary, has been reported to produce unusual motor and behavioural effects and may act as a regulatory neuropeptide, not as a classical opiate agonist or antagonist. We have therefore administered to cats in which the right middle cerebral artery had been occluded both dynorphin (1-13) and analogue and control materials. We find that dynorphin (1-13) prolongs survival.     

A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin releaser.

It is generally accepted that morphine exerts its analgesic effect by binding to specific opiate receptors in the brain and spinal cord. Since Hughes et al. isolated and identified two endogenous pentapeptides, Met- and Leu-enkephalin, from the brain and found that they acted as agonists at opiate receptors, alpha-, beta- and gamma-endorphins, larger peptides than enkephalins and having morphine-like activity, have been identified in either the brain or pituitary of various species. Several studies have demonstrated that enkephalins possess analgesic properties and that they are distributed in the pain-mediated pathways in the central nervous system. These findings suggest that enkephalins are important neurotransmitters or neuromodulators regulating pain transmission. We now report the isolation of a novel substance which has a Met-enkephalin releasing action. Our findings suggest the possibility of a regulating mechanism for the release of endogenous opioid peptides, especially Met-enkephalin.     

Anti-nociceptive role of neuropeptide Y in the nucleus accumbens in rats with inflammation, an effect modulated by mu- and kappa-opioid receptors

Recent study in our laboratory showed that neuropeptide Y (NPY) plays an antinociceptive role in the nucleus accumbens (NAc) in intact rats. The present study was performed to further investigate the effect of NPY in nociceptive modulation in the NAc of rats with inflammation, and the possible interaction between NPY and the opioid systems. Experimental inflammation was induced by subcutaneous injection of carrageenan into the left hindpaw of rats. Intra-NAc administration of NPY induced a dose-dependent increase of hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations in rats with inflammation. The anti-nociceptive effect of NPY was significantly blocked by subsequent intra-NAc injection of the Y1 receptor antagonist NPY28-36, suggesting an involvement of Y1 receptor in the NPY-induced anti-nociception. Furthermore, intra-NAc administration of the opioid antagonist naloxone significantly antagonized the increased HWLs induced by preceding intra-NAc injection of NPY, suggesting an involvement of the endogenous opioid system in the NPY-induced anti-nociception in the NAc during inflammation. Moreover, the NPY-induced anti-nociception was attenuated by following intra-NAc injection of the μ-opioid antagonist β-funaltrexamine (β-FNA), and κ-opioid antagonist nor-binaltorphimine (nor-BNI), but not by δ-opioid antagonist naltrindole, indicating that μ- and κ-opioid receptors, not δ-opioid receptor, are involved in the NPY-induced anti-nociception in the NAc in rats with inflammation.     

Osmotic stress mimics effects of vasopressin on learned behaviour

It has been suggested that arginine vasopressin (AVP) is involved in the retention of learned responses, in addition to its classical physiological functions of water retention and modulation of blood pressure. AVP administered subcutaneously (s.c.), intraventricularly or intracerebrally can prolong extinction of active avoidance behaviour and can enhance retention in inhibitory (passive) avoidance. These effects have been interpreted as a direct action of AVP on the central nervous system to facilitate memory consolidation. AVP also has facilitatory effects on cognitive function in humans, and marked deficits in AVP function have been associated with certain types of psychopathology. Alternative hypotheses for the behavioural actions of AVP have involved motivational constructs such as arousal, and our recent work has focused on the role of arousal resulting from the activation of peripheral visceral signals in the behavioural effects of peripherally administered AVP. The development of a specific antagonist for AVP, 1-deaminopenicillamine-2-O-methyl tyrosine arginine vasopressin (dPTyr(Me)AVP), which can reverse the behavioural effects of exogenously administered AVP, has provided a powerful tool for examining the role of AVP in the behavioural responses produced by physiological challenges known to release vasopressin. However, the relationship between the behavioural effects of exogenously administered AVP and the behavioural function of endogenously released AVP has not been evaluated. We report here that a potent peripheral osmotic stimulus, the intraperitoneal (i.p.) injection of hypertonic saline, at doses known to release AVP both centrally and peripherally, will produce behavioural effects similar to those of exogenously administered AVP. Furthermore, the prolongation of active avoidance induced by this osmotic stimulus is reversed by pretreatment with dPTyr(Me)AVP, suggesting that endogenously released AVP may also produce behavioural effects.     

Sustained division of the attentional spotlight

By voluntarily directing attention to a specific region of a visual scene, we can improve our perception of stimuli at that location. This ability to focus attention upon specific zones of the visual field has been described metaphorically as a moveable spotlight or zoom lens that facilitates the processing of stimuli within its 'beam'. A long-standing controversy has centred on the question of whether the spotlight of spatial attention has a unitary beam or whether it can be divided flexibly to disparate locations. Evidence supporting the unitary spotlight view has come from numerous behavioural and electrophysiological studies. Recent experiments, however, indicate that the spotlight of spatial attention may be divided between non-contiguous zones of the visual field for very brief stimulus exposures (&<100 ms). Here we use an electrophysiological measure of attentional allocation (the steady-state visual evoked potential) to show that the spotlight may be divided between spatially separated locations (excluding interposed locations) over more extended time periods. This spotlight division appears to be accomplished at an early stage of visual-cortical processing.     

Coffee contains potent opiate receptor binding activity

Opiate receptor-active peptide fragments (exorphins) have been identified recently in casein and gluten hydrolysates, and morphine has been found in bovine and human milk. To determine whether similar peptides or alkaloids occur in other foodstuffs, we have screened potential sources using a rat brain homogenate assay to detect opiate receptor activity. We report here that instant coffee powders from a variety of manufacturers compete with tritiated naloxone for binding to opiate receptors in the rat brain membrane preparations, with no significant difference between normal and decaffeinated coffee. The receptor binding activity resembles that seen with opiate antagonists, in that there was no change in the half-maximal effective dose (ED50) in the presence of 100 mM Na+; on bioassay, the activity was similarly shown to be antagonistic and specific for opiate-induced inhibition of twitch. Preliminary characterization of the activity reveals that it has a molecular weight (MW) in the range 1,000-3,500, is heat-stable, ether-extractable, not modified by enzymatic digestion with papain, and clearly separable from caffeine and morphine on TLC. As its concentration in an average cup of coffee is five times the ED50, these data suggest that drinking coffee may be followed by effects mediated via opiate receptors, as well as effects of caffeine.     

Predator-induced behaviour shifts and natural selection in field-experimental lizard populations

The role of behaviour in evolutionary change has long been debated. On the one hand, behavioural changes may expose individuals to new selective pressures by altering the way that organisms interact with the environment, thus driving evolutionary divergence. Alternatively, behaviour can act to retard evolutionary change: by altering behavioural patterns in the face of new environmental conditions, organisms can minimize exposure to new selective pressures. This constraining influence of behaviour has been put forward as an explanation for evolutionary stasis within lineages and niche conservatism within clades. Nonetheless, the hypothesis that behavioural change prevents natural selection from operating in new environments has never been experimentally tested. We conducted a controlled and replicated experimental study of selection in entirely natural populations; we demonstrate that lizards alter their habitat use in the presence of an introduced predator, but that these behavioural shifts do not prevent patterns of natural selection from changing in experimental populations.     

beta-Carboline-3-carboxylic acid ethyl ester antagonizes diazepam activity

Analogous to the progression of events in the opiate receptor-enkaphalin area, the first reports that benzodiazepines have selective and specific high-affinity binding sites in brain have stimulated a search for the endogenous 'ligand' or substance that might normally act at these sites. Braestrup and co-workers have extracted from human urine a gamma-fraction (ref. 10) which they have recently identified as beta-carboline-3-carboxylic acid ethyl ester (beta CEE). They reported that this substance is extremely potent in displacing 3H-diazepam from brain binding sites and proposed that a beta-carboline-3-carboxylic acid derivative might, in part, be the endogenous ligand for the brain benzodiazepine receptor. We have examined several synthetically derived beta-carboline-3-carboxylic acid analogues and now present data obtained from testing only the beta CEE described by Braestrup et al. In addition to confirming these workers' observation that this compound is a potent displacer of 3H-diazepam from brain tissue, our pharmacological data indicate that beta CEE has activity that is opposite to, rather than similar to, that of diazepam.     

The endogenous cannabinoid system controls extinction of aversive memories

Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.     

Neurotransmitter turnover in rat striatum is correlated with morphine self-administration

Drugs of abuse probably exert their reinforcing effects through 'reward' pathways in the central nervous system (CNS). Neuronal systems mediating opiate reinforcement have been investigated using pharmacological and electrolytic lesion procedures. Drugs that interfere with catecholaminergic and cholinergic neuronal activity decrease intravenous (i.v.) morphine self-administration in monkeys and rats. Electrolytic lesion procedures in rats have demonstrated that the medial forebrain bundle and caudate nucleus are important in maintaining i.v. morphine self-administration. We have now carried out a direct investigation of striatal (caudate nucleus, putamen and globus pallidus) neuronal systems. We show here that striatal catecholaminergic systems are important in mediating opiate reinforcement, and present direct evidence for the involvement of neurotransmitter systems in morphine reward.     

Interactions between working memory and selective attention

Event-related potential (ERP) was used to examine the interactions between working memory and se- lective attention. We combined two unrelated tasks, one requiring working memory and the other se- lective attention, which were performed by some undergraduates. The ERP results revealed that both congruent and incongruent stimuli in the selective attention task evoked an N400 component, reaching the peak point at around 500 ms. The N400 evoked by incongruent stimuli was more negative than that of congruent, which indicated the difference of semantic N400. Furthermore, working memory load had a significant influence on the N400 evoked by selective attention task in parietal region. And working memory load showed difference in the ERPs of working memory retrieval in central and parietal regions. The ERPs of probe under high working memory load were more positive from 350 to 550 ms post-stimulus; however, stimulus type of selective attention had no influence on working memory re- trieval. The present study shows that working memory does not play a major role in the selective at- tention, especially in ignoring distracter, but it influences the performance of the selective attention as the background. The congruency of target and distracter in the selective attention task does not influ- ence the working memory retrieval.     

Naloxone-reversible effect of opioids on pinocytosis in Amoeba proteus

A characteristic feature of induced pinocytosis in Amoeba proteus is the formation of broad channels by invagination of the cell membrane. This process, which requires Ca2+, occurs in response to depolarising cations. High Ca2+ levels reduce pinocytosis induced by cations such as Na+ and Tris+, whereas pinocytosis induced by K+ is less affected by Ca2+ (ref. 4). Agents which interfere with the calcium metabolism of the amoeba will therefore either stimulate or inhibit pinocytosis induced by Na+ (ref. 5). Among the agents which are supposed to reduce Ca2+ influx across cell membranes or otherwise decrease cellular availability of Ca2+ are the opiates and opioid peptides, high doses of which have been reported to affect the amoeba. Accordingly, Met-enkephalin, morphine and codeine potentiate the inhibition of pinocytosis caused by Ca2+-binding agents and reverse the calcium blockade of pinocytosis mediated by caffeine. In this report we show that pinocytosis induced by Na+ or Tris+ is suppressed by beta-endorphin, Metenkephalin and morphine. These effects were abolished or diminished by an opiate receptor antagonist, (-)naloxone, by increasing the Na+ concentration, or by addition of Ca2+.     

Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion

Cessation of drug use in chronic opiate abusers produces a severe withdrawal syndrome that is highly aversive, and avoidance of withdrawal or associated stimuli is a major factor contributing to opiate abuse. Increased noradrenaline in the brain has long been implicated in opiate withdrawal, but it has not been clear which noradrenergic systems are involved. Here we show that microinjection of beta-noradrenergic-receptor antagonists, or of an alpha2-receptor agonist, into the bed nucleus of the stria terminalis (BNST) in rats markedly attenuates opiate-withdrawal-induced conditioned place aversion. Immunohistochemical studies revealed that numerous BNST-projecting cells in the A1 and A2 noradrenergic cell groups of the caudal medulla were activated during withdrawal. Lesion of these ascending medullary projections also greatly reduced opiate-withdrawal-induced place aversion, whereas lesion of locus coeruleus noradrenergic projections had no effect on opiate-withdrawal behaviour. We conclude that noradrenergic inputs to the BNST from the caudal medulla are critically involved in the aversiveness of opiate withdrawal.     

Opposite motivational effects of endogenous opioids in brain and periphery

Many psychoactive drugs, including the opiates, have been shown to have paradoxical reinforcing effects. Opiates produce positive reinforcing effects when they are paired with visual and textural environmental stimuli in rats, yet, at similar doses and over the same routes of administration, produce aversive effects, as shown when they are paired with taste stimuli. Similarly, in human, the positive reinforcing effects of opiates are well known to addicts and recreational drug users, yet patients receiving opiates as analgesics often report nauseous reactions. At present there is no evidence to differentiate between the neural substrates that mediate these opposite motivational effects. We now report an initial step in the resolution of this paradox by demonstrating that endogenous and exogenous opioids produce positive reinforcing effects through an action on brain opiate receptors, and aversive effects through an action on peripheral opiate receptors (especially in the gut).     

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.     

Exocytotic fusion is activated by Rab3a peptides.

Studies of intracellular traffic in yeast and mammalian systems have implicated members of the Rab family of small GTP-binding proteins as regulators of membrane fusion. We have used the patch clamp technique to measure exocytotic fusion events directly and investigate the role of GTP-binding proteins in regulating exocytosis in mast cells. Intracellular perfusion of mast cells with GTP-gamma S is sufficient to trigger complete exocytotic degranulation in the absence of other intracellular messengers. Here we show that GTP is a potent inhibitor of GTP-gamma S-induced degranulation, indicating that sustained activation of a GTP-binding protein is sufficient for membrane fusion. We have found that synthetic oligopeptides, corresponding to part of the effector domain of Rab3a, stimulate complete exocytotic degranulation, similar to that induced by GTP-gamma S. The response is selective for Rab3a sequence and is strictly dependent on Mg2+ and ATP. This suggests that sustained activation of a Rab3 protein causes exocytotic fusion. The peptide response can be accelerated by GDP-beta S, suggesting that Rab3a peptides compete with endogenous Rab3 proteins for a binding site on a target effector protein, which causes fusion on activation.     

Improved auditory spatial tuning in blind humans.

Despite reports of improved auditory discrimination capabilities in blind humans and visually deprived animals, there is no general agreement as to the nature or pervasiveness of such compensatory sensory enhancements. Neuroimaging studies have pointed out differences in cerebral organization between blind and sighted humans, but the relationship between these altered cortical activation patterns and auditory sensory acuity remains unclear. Here we compare behavioural and electrophysiological indices of spatial tuning within central and peripheral auditory space in congenitally blind and normally sighted but blindfolded adults to test the hypothesis (raised by earlier studies of the effects of auditory deprivation on visual processing) that the effects of visual deprivation might be more pronounced for processing peripheral sounds. We find that blind participants displayed localization abilities that were superior to those of sighted controls, but only when attending to sounds in peripheral auditory space. Electrophysiological recordings obtained at the same time revealed sharper tuning of early spatial attention mechanisms in the blind subjects. Differences in the scalp distribution of brain electrical activity between the two groups suggest a compensatory reorganization of brain areas in the blind that may contribute to the improved spatial resolution for peripheral sound sources.     

新皮啡肽Ⅰ对大鼠免疫功能的影响

新皮啡肽Ⅰ（DELⅠ）在离体条件（浓度范围10^-14-10^-10mol/L)和活体条件（剂量范围0．5－5μg/kg)下能提高红细胞玫瑰花环形成细胞百分率（E－RFC）和红细胞C3b受体花环百分率（RBC－CR1）,这种效应可被纳洛酮拮抗.这些结果表明DELⅠ提高了大鼠免疫功能,这种作用可能由阿片受体介导。     

物理兴趣的激发及其对素质教育的作用

应试教育向素质教育转化是高校教育改革的要求 ,高校物理教学中学生学习兴趣的激发对提高学生素质具有十分重要的作用 .兴趣的激发 ,不是浅层的感性的直接兴趣的激发 ,而是一种稳定的理性的深层次的间接兴趣的激发 .从教师的主导和学生的主体两方面入手 ,紧抓学生的心理 ,突出情感的作用 ,使学生的学习兴趣从被激到内化 ,从一种心理过程转化为一种心理品质 ,实现从兴趣激发到培养学生素质的目的