Orexinergic System Research Articles

Involvement of the Brain Orexinergic System in Sleep–Wake Cycle Regulation

The paper considers recent studies of brain orexinergic system in animals and humans. The considered neurotransmitter system is involved in the regulation of a wide spectrum of brain responses occurring in living organisms during wakefulness. This study reflects the current concept of the triggering role of orexins A and B in initiation of awakening and cites scientific opinions of a number of leading researchers on the studied problem. Orexin-containing neurons located in the hypothalamus play one of the top roles in the regulation of brain aminergic systems during active wakefulness. The summary of scientific data accumulated in the past ten years makes it possible to sufficiently extend the existing concepts of the sleep–wake cycle regulation mechanisms. The progress in revealing relationships and events in the brain that are necessary for normal sleep–wake changeover forms the basis for developing new methods for correction of disorders of these processes.

Ionic Mechanisms Underlying the Excitatory Effect of Orexin on Rat Subthalamic Nucleus Neurons.

Central orexinergic system deficiency results in cataplexy, a motor deficit characterized with a sudden loss of muscle tone, highlighting a direct modulatory role of orexin in motor control. However, the neural mechanisms underlying the regulation of orexin on motor function are still largely unknown. The subthalamic nucleus (STN), the only excitatory structure of the basal ganglia, holds a key position in the basal ganglia circuitry and motor control. Previous study has revealed a wide distribution of orexinergic fibers as well as orexin receptors in the basal ganglia including the STN. Therefore, in the present study, by using whole-cell patch clamp recording and immunostaining techniques, the direct effect of orexin on the STN neurons in brain slices, especially the underlying receptor and ionic mechanisms, were investigated. Our results show that orexin-A elicits an excitatory effect on STN neurons in rats. Tetrodotoxin (TTX) does not block the orexin-induced excitation on STN neurons, suggesting a direct postsynaptic action of the neuropeptide. The orexin-A-induced inward current on STN neurons is mediated by the activation of both OX1 and OX2 receptors. Immunofluorescence result shows that OX1 and OX2 receptors are co-expressed and co-localized in STN neurons. Furthermore, Na+-Ca2+ exchangers (NCXs) and inward rectifier K+ channels co-mediate the excitatory effect of orexin-A on STN neurons. These results demonstrate a dual receptor in conjunction with the downstream ionic mechanisms underlying the excitatory action of orexin on STN neurons, suggesting a potential modulation of the central orexinergic system on basal ganglia circuitry as well as its related motor control and motor diseases.

Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice.

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-α) mRNA expression via histamine H4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-α impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H4 receptor antagonist (JNJ7777120, 10mg/kg) inhibited the decrease in expression. The effect of the H4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX2 receptor antagonist (JNJ10397049, 5mg/kg) rather than an orexin OX1 receptor antagonist (SB408124, 30mg/kg). Although an OX2 receptor agonist (YNT-185, 20mg/kg) or a histamine H3 receptor inverse agonist (ciproxifan, 1mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX2 receptor agonist was antagonized by an H3 receptor silent antagonist (VUF5681, 5mg/kg). The combination of JNJ7777120 (10mg/kg) and ciproxifan (0.5mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia.

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

Orexin A depolarises rat intergeniculate leaflet neurons through non-selective cation channels.

Orexins/hypocretins are hypothalamic neuropeptides that have a variety of functions, including maintenance of arousal, control over the sleep/wake cycle, reward and feeding. Accumulating evidence links orexins to the time-keeping system with a documented action in the master clock-the suprachiasmatic nucleus. The intergeniculate leaflet (IGL) is a thalamic structure with the well-known function of collecting photic and non-photic cues to adjust the rhythm of the suprachiasmatic nucleus to changing environmental conditions. The IGL consists of GABAergic neurons that are intrinsically active, even in slice preparations. Our previous studies revealed the excitatory postsynaptic effects of orexins on single IGL neurons, even though the ionic mechanism underlying this effect remained elusive. Therefore, in this study, we used patch clamp electrophysiology to identify the ions and distinct ion channels responsible for the observed depolarisations. The major finding of this article is that the orexin A-evoked depolarisation of IGL neurons depends on non-selective cation channels, implicating the orexinergic tone in establishing the basal firing rate in these cells. The data presented here strengthen the mutual connections between the time-keeping and orexinergic systems.

Spinal Orexin-2 Receptors are Involved in Modulation of the Lateral Hypothalamic Stimulation-Induced Analgesia.

Role of the orexinergic system in pain modulation is well studied and involvement of the spinal orexin-1 receptors is well documented. In this study, we examined role of the spinal orexin-2 receptors in modulation of inflammatory pain in rat. Fifty-one adult male Wistar rats were implanted unilaterally with a guide cannula into the LH and intrathecal tubing in the lumbar space between L4 and L5. Chemical stimulation of LH by carbachol (250nM/0.5µL saline) induced remarkable analgesia during the two phases of formalin test and Intrathecal administration of different doses of TCS OX2 29 (10, 30 and 100µM/ 0.5µL DMSO) prior to LH stimulation, dose-dependently antagonized the antinociceptive effect of the LH-stimulation during the two phases of formalin test. The effect size of the TCS OX2 29 was η2 = 0.47 and η2 = 0. 87 for the early and late phases of the test, respectively. Also, intrathecal administration of TCS OX2 29 alone (without stimulation of the LH) had no significant effect on formalin induced pain-related behaviors. Our results showed that spinal orexin-2 receptors are involved in modulation of the LH-stimulation induced analgesia in a persistent inflammatory pain model. These findings may suggest spinal orexin-2 receptors in particular and the orexin system in general as a useful therapeutic target for treatment of chronic pains.

Functional crosstalk of nucleus accumbens CB1 and OX2 receptors in response to nicotine-induced place preference

In the present study, we have evaluated the existence of functional interaction between orexin-2 receptor (OX2R) and cannabinoid-1 receptor (CB1R) in the nucleus accumbens core (NAcc), in nicotine-induced conditioned place preference (CPP) of Wistar male rat. Nicotine (0.5 mg/kg; s.c.) in the course of conditioning, produced a significant place preference, without any effect on the locomotor activity. Intra-NAcc administration of ineffective and effective doses of TCS-OX2-29 (2 and 6 ng/rat), a selective OX2R antagonist and AM251 (10 and 50 ng/rat), a selective CB1R antagonist, showed a significant interaction between OX2R and CB1R in the acquisition of nicotine-induced CPP (p < 0.01), and the locomotor activity (p < 0.05). No significant interaction was observed between these two receptors in the expression of nicotine-induced CPP. Our findings provide insight into the possible interaction of OX2R and CB1R of the NAcc in nicotine addiction. We propose a potential interaction between cannabinoid and orexinergic systems within the NAcc, in producing the rewarding effects.

Obstructive sleep apnea may induce orexinergic system and cerebral β-amyloid metabolism dysregulation: is it a further proof for Alzheimer's disease risk?

BackgroundObstructive Sleep Apnea (OSA) is associated with pathological changes of cerebral β-amyloid dynamics. Orexin has been demonstrated interfering with β-amyloid metabolism in Alzheimer's Disease (AD) pathology. The present study investigated cerebrospinal-fluid (CSF) β-amyloid40 (Aβ40), β-amyloid42 (Aβ42) and orexin levels in OSA patients compared to AD patients and controls. MethodsOSA and AD patients were included in this study and compared to a group of controls. Patients and controls underwent lumbar puncture for the assessment of CSF Aβ40, Aβ42, tau proteins, orexin levels, and polysomnography to measure nocturnal sleep architecture. Results20 OSA patients, 20 AD patients, and 15 controls were included in our study. OSA patients showed higher CSF orexin levels than AD patients and controls, and AD patients showed higher CSF orexin levels than controls. Moreover, CSF Aβ40 and Aβ42 were lower in OSA patients than controls, but higher in OSA patients compared to AD patients. However, AD patients showed lower CSF Aβ42 levels but comparable CSF Aβ40 levels than controls. Sleep macrostructure was similarly altered in OSA and AD patients compared to controls. Finally, the apnea-hypopnea index (AHI) was related to the ratio Aβ42/Aβ40 and CSF orexin levels in OSA patients. ConclusionThis study proved the alteration of CSF orexin levels and β-amyloid isoforms 40 and 42 in OSA patients. We suppose that sleep disruption and intermittent hypoxia, the two core features of OSA, may induce orexinergic system and cerebral β-amyloid metabolism dysregulation. This evidence further supports the current hypothesis that OSA may possibly start AD neuropathological processes.

Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration.

Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.

Влияние пренатального стресса на формирование орексинергической системы гипоталамуса крысы

The influence of prenatal stress (PNS) on the development of the orexinergic and dopaminergic systems of the brain in 14 and 30-day-old Wistar rats were studied. Pups were born by females, which E13-E19 were subjected to sleep deprivation (6 hours a day) by «small platforms» method. In P14 PNS pups the violations of locomotion development were revealed by the «open field» test. In the hypothalamus a significant increase in orexin A in the periphornical area neurons was detected on the brain slices by immunohistochemical method. A high performance liquid chromatography showed the increase of dopamine level and a rate of its metabolism vs. control pups born from intact females. The results of Western-blotting demonstrate in striatum the decrease of enzyme of GABA synthesis (GAD65) and increase of level of phosphorylated tyrosine hydroxylase (serin-40) – enzyme of dopamine synthesis vs. control. In P30 the locomotion activity of PNS pups do not differ from the control, but the PNS pups are characterized by a higher level of anxiety and lower behavior. The results of morphological and biochemical studies also indicate the absence of differences in the studied parameters in the hypothalamus and in the striatum in P30 PNS pups vs. the control. The data is confirmed by the results of the electrophysiological study, which also demonstrates the absence of differences in the organization of the wakefulness-sleep cycle in the P30 PNS and control pups. The article discusses the morphofunctional interactions of the orexinergic and dopaminergic systems of the brain in the early postnatal period of the organism development and the role of orexins in the compensatory mechanisms of the brain. Key words: brain, hypothalamus, striatum, ontogenesis, prenatal stress, orexin, dopamine, locomotion activity, wakefulness-sleep cycle.

Орексин-А и его рецепторы в гипоталамусе мышей с диета-индуцированным и меланокортиновым ожирением

Orexin-A is one of the regulators of food intake and energy metabolism. In the brain, this peptide is formed in the neurons of the perifornical hypothalamic area from prepro-orexin, and its action is realized through two types of orexin receptors (OX1R, OX2R). In the diet-induced obesity (DIO), the activity of the hypothalamic orexin system changes, but the data on the orexin-А level and the expression of OX1R and OX2R are few and contradictory. In the case of melanocortin obesity, these data are not available. The aim of the work was to study the orexinergic system in the hypothalamus of mice with the different forms of obesity: with DIO, induced by a high-calorie diet (8 and 16 weeks) in C57Bl/6J (a/a) mice, and agouti mice, C57Bl/6J (Ay/a), with genetically determined melanocortin obesity. The level of orexin-A in neurons was evaluated in brain sections by immunohistochemistry; the gene expression of prepro-orexin (pOx), Ox1r and Ox2r in the hypothalamus was measured by quantitative PCR. In DIO mice, the level of orexin-A and the expression of the pOx and Ox1r genes in the hypothalamus were changed depending on the duration of the diet: increased after 8 weeks and returned to the control values after 16 weeks. At the same time, the expression of the Ox2r gene did not change. In agouti mice, a decrease in the immunopositive orexin-A level in the perifornical area neurons of the hypothalamus was shown. The expression of the pOx, Ox1r and Ox2r genes in the hypothalamus of agouti mice did not change significantly. The findings suggest that reducing orexin-A level in conditions of prolonged, heavy obesity may be a compensatory response aimed at reducing calorie intake, and the orexin system of the hypothalamus can be considered as one of the targets for correcting and preventing the different forms of obesity.

Modafinil and orexin system: interactions and medico-legal considerations.

Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser.

Involvement of orexin-2 receptor in the ventral tegmental area in stress- and drug priming-induced reinstatement of conditioned place preference in rats

Orexin neurons originate from the lateral hypothalamus and send their projections broadly throughout the central nervous system including to the ventral tegmental area (VTA). In the current study, the reinstatement model has been used to examine the effects of intra-VTA administration of TCS-OX2-29, an orexin-2 receptor (OX2R) antagonist, on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine-induced conditioned place preference (CPP). A total of 73 adult male Wistar rats weighing 200–280 g were bilaterally implanted with cannulas into the VTA. For induction of CPP, subcutaneous (sc) injection of morphine (5 mg/kg) was done daily during a 3-day conditioning phase. After a 24-h “off” period following achievement of extinction criterion, the rats were tested for drug priming-induced reinstatement with a priming dose of morphine (1 mg/kg;sc) or after application of FSS on the reinstatement day. The animals then received different doses of the OX2R antagonist, TCS-OX2-29 (0.3,3,1 and 10 nM) bilaterally in the VTA (0.3 μl/side) and were tested for FSS- and morphine priming-induced reinstatement of CPP. Our findings indicate that intra-VTA administration of OX2R antagonist suppresses FSS and morphine priming-induced reinstatement in a dose-dependent manner. The role of the orexinergic system in morphine-induced reinstatement through activation of OX2R in the VTA provides evidence that the OX2R antagonist could be a useful therapeutic target for prevention of reinstatement of morphine-induced CPP.

Cerebrospinal Fluid Orexin Levels and Nocturnal Sleep Disruption in Alzheimer's Disease Patients Showing Neuropsychiatric Symptoms.

Alzheimer's disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients. The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography. This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score ≥4, AD/NPS+) or absence (NPI score <4, AD/NPS-) of NPS. Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS-group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS-patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS-patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores. This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on neurobehavioral disturbances.

The Orexinergic (Hypocretin) System and Nociception: An Update to Supraspinal Mechanisms.

Chronic pain is a multifaceted and complex condition that is divided into somatic, visceral, and neuropathic pain. Although opioids and nonsteroidal anti-inflammatory drugs cause analgesia and are effective in the treatment of chronic pain, their utility is hampered by side effects, abuse potential, and development of tolerance to their pain-relieving effects. So, finding alternative analgesics with good efficacy and low side effects is of great interest and the orexinergic system is a potential candidate. Orexin-A and -B are exclusively expressed in the lateral hypothalamus and are involved in the feeding, sleep/wake cycle, cardiovascular function, hormone secretion, seizure, and pain modulation. Orexin peptides and their receptors have been proposed as opportunities for developing analgesic drugs. In experimental studies, orexin peptides induce analgesia that is comparable to morphine. Furthermore, there is evidence that orexin receptors 1 and 2 participate in responsiveness to both stressful stimuli and pain. Thus, direct and indirect activation of the orexinergic system is a new therapeutic approach to pain control. This article will review the most recent and important studies describing the role of orexins in pain modulation.

Influence of Orexinergic System on Survival in Septic Rats

Background: The orexinergic (OXergic) system contributes to the defense system. It has also been reported that the degeneration of OXergic neurons occurs during sepsis. Thus, the decline of OXergic activity may contribute to impairment of the defense system in sepsis. In this study, we determined whether: (i) lipopolysaccharide (LPS) reduces the brain orexin A (OXA) content and (ii) the OXergic system contributes to survival from sepsis in rats. Methods: With approval of our protocol by our University Animal Ethics Committee, OX neuron-ablated (OX/ataxin-3 transgenic [OX/AT3 TG]) and wild-type Sprague-Dawley rats, weighing 250–350 g, were used. LPS (10 mg/kg) was administered intraperitonally to the wild-type rats (group SD, n = 26) and OX/AT3 TG rats (group TG, n = 14). Another 7 SD rats were included as a saline control (group C). Survival analysis was then performed over a period of 3 days. All surviving rats were decapitated and the brain OXA contents (from the cerebrocortex, hippocampus, hypothalamus, and pons) were quantified using ELISA kits. Results: In group SD, 61.5% rats survived, while in group TG, only 21.4% survived (p < 0.05). LPS significantly reduced OXA content (pg/mg of tissue) in group SD (2.92 ± 0.38) compared to in group C (4.10 ± 1.21) in the pons (p < 0.05). OXA content in group TG was substantially lower than in group C and group SD in all brain regions. Conclusions: LPS significantly reduced OXA contents in the pons which contains the locus coeruleus to regulate sympathetic activity in the defense system.

Involvement of orexinergic receptors in the nucleus accumbens, in the effect of forced swim stress on the reinstatement of morphine seeking behaviors

Orexinergic system is involved in primary rewards; the neural circuit of the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex and amygdala represents overlapping elements mediating the rewarding effects of drugs and stressful experiences. The NAc integrates reward-related information from the VTA. Also, it has been indicated that orexinergic system activates the mesolimbic dopamine projecting neurons to the NAc and promotes the development of reward in rodents. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to determine the role of the two types of orexin receptors (OXR) in the NAc in forced swim stress (FSS), as physical stress, and/or priming-induced reinstatement of morphine. The CPP was induced by injecting morphine (5 mg/kg, SC for 3 days) and lasted for eight free-morphine days; the reinstatement was induced by administration of effective priming dose of morphine (1 mg/kg; sc). The extinguished rats received intra-NAc injection of SB334867 as OX1R antagonist or TCSOX229 as OX2R antagonist before effective priming dose injection of morphine (1 mg/kg; sc). In others, the extinguished rats were given intra-NAc injection of SB334867 or TCSOX229 and then, they underwent FSS before injection of ineffective priming dose of morphine (0.5 mg/kg; sc). Our results showed that intra-accumbal administration of SB334867 or TCSOX229 could inhibit morphine priming- and FSS-induced reinstatement of extinguished morphine-seeking in the rats. It seems that OXR in the NAc may be involved in reward and could play an important role in the effect of stress on reinstatement of morphine-seeking behaviors in this area.

Orexin prevents depressive-like behavior by promoting stress resilience

Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na+–Ca2+ exchanger and L-type Ca2+ channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.

Orexin-1 receptor is involved in ageing-related delayed emergence from general anaesthesia in rats

BackgroundPrevious clinical studies have shown that emergence from isoflurane anaesthesia takes longer in elderly patients compared with middle-aged patients. The current study investigated whether delayed emergence from anaesthesia in older age is associated with the age-related decrease in orexin receptors by using a rat model. MethodsAdult and aged Sprague–Dawley rats were used to assess the time to emergence after 30 min isoflurane anaesthesia (1.4 vol%), and differences in the orexinergic systems, including the number of orexinergic neurones, plasma orexin concentrations, and expression of orexin-1 (OX1R) and orexin-2 receptors, compared using immunofluorescence, radioimmunoassay, western blot, and real-time polymerase chain reaction. The effects of OX1R expression on emergence time were determined by virus-mediated overexpression of OX1R using intra-cerebroventricular injection. ResultsThe median (range) emergence time of aged rats was longer than that in adult rats [1082 (1010–1130) compared with 848 (829–938) s; P=0.0009]. Plasma orexin concentrations were higher in the aged group than the adult group [34 (33–37) and 25 (22–31) pg ml−1, respectively; P=0.04], but the number of orexinergic neurones was similar in both groups. Protein expression of OX1R was lower in the aged group compared with the adult group [0.47 (0.35–0.58) compared with 0.97 (0.86–1.32), respectively; P=0.002]. Overexpression of OX1R significantly shortened the emergence time in aged rats from [1120 (1040–1190) s] to [769 (576–928) s; P=0.03]. ConclusionsAge-related decrease in OX1R expression is associated with delayed emergence from isoflurane anaesthesia in aged rats.

Cellular and Molecular Bases of Changes to Neuroimmune Interactions in Stress

This article presents current views on the cellular and molecular bases of the central mechanisms of neuroimmune interactions, along with data on the effects of destabilizing factors (painful electrical stimulation, cold, psychoemotional stress) on the functions of neurons and immunocompetent cells. It is important to emphasize that stress is associated with changes in ligand-receptor interactions on the membranes of lymphoid cells which respond to the interleukin-1 regulatory signal; these changes consist either of enhanced responses to this regulatory signal (in mild stress situations) or sharp decreases in responses (on exposure to strongly stressful factors). Special attention is paid to the role of the orexinergic system in the mechanisms mediating the brain’s responses to administration of antigens and exposure to stressors. We consider possible means of correcting the imbalance in the functional interaction between the nervous and immune systems occurring as a result of various destabilizing factors.