OBJECTIVES: To investigate the effect of orexin-A-mediated regulation of ionotropic glutamate receptors for promoting motor function recovery in rats with spinal cord injury (SCI). METHODS: Thirty-six newborn SD rats (aged 7-14 days) were randomized into 6 groups (n=6), including a normal control group, a sham-operated group, and 4 SCI groups with daily intrathecal injection of saline, DNQX, orexin-A, or orexin-A+DNQX for 3 consecutive days after PCI. Motor function of the rats were evaluated using blood-brain barrier (BBB) score and inclined plane test 1 day before and at 1, 3, and 7 days after SCI. For patch-clamp experiment, spinal cord slices from newborn rats in the control, sham-operated, SCI, and SCI+orexin groups were prepared, and ventral horn neurons were acutely isolated to determine the reversal potential and dynamic indicators of glutamate receptor-mediated currents under glutamate perfusion. RESULTS: At 3 and 7 days after SCI, the orexin-A-treated rats showed significantly higher BBB scores and grip tilt angles than those with other interventions. Compared with those treated with DNQX alone, the rats receiving the combined treatment with orexin and DNQX had significantly higher BBB scores and grip tilt angles on day 7 after PCI. In the patch-clamp experiment, the ventral horn neurons from SCI rat models exhibited obviously higher reversal potential and greater rise slope of glutamate current with shorter decay time than those from sham-operated and orexin-treated rats. CONCLUSIONS Orexin-A promotes motor function recovery in rats after SCI possibly by improving the function of the ionotropic glutamate receptors.
Animals ; Spinal Cord Injuries/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, Ionotropic Glutamate/metabolism* ; Recovery of Function/drug effects* ; Orexins/pharmacology* ; Male ; Female ; Animals, Newborn ; Neuropeptides/pharmacology* ; Intracellular Signaling Peptides and Proteins/pharmacology*

Cognitive impairment is a common consequence of narcolepsy type 1 （NT1）， seriously affecting the patients' learning and working. Research evidence has indicated that patients with NT1 exhibit substantial deficits in cognitive domains such as attention， memory， and executive function. The specific mechanisms underlying cognitive impairment in NT1 remain unclear. Animal studies have revealed a close association of insufficient orexin levels in cerebrospinal fluid with cognitive dysfunction. Recent neuroimaging studies with different methodologies have unraveled structural and functional abnormalities in cognitive dysfunction caused by NT1. To date， evidence-based treatment for NT1-associated cognitive impairment is still lacking. This article provides a review of the progress on cognitive impairment in NT1.
Orexins

OBJECTIVE: This study investigates the sleep-modulating effects of ginsenoside Rg1 (Rg1, C₄₂H₇₂O₁₄), a key bioactive component of ginseng, and elucidates its underlying mechanisms. METHODS: C57BL/6J mice were intraperitoneally administered doses of Rg1 ranging from 12.5 to 100 mg/kg. Sleep parameters were assessed to determine the average duration of each sleep stage by monitoring the electrical activity of the brain and muscles. Further, orexin neurons in the lateral hypothalamus (LH) and corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (PVH) were ablated using viral vector surgery and electrode embedding. The excitability of LH^orexin and PVH^CRH neurons was evaluated through the measurement of cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-Fos) expression. RESULTS: Rg1 (12.5-100 mg/kg) augmented the duration of non-rapid eye movement (NREM) sleep phases, while reducing the duration of wakefulness, in a dose dependent manner. The reduced latency from wakefulness to NREM sleep indicates an accelerated sleep initiation time. We found that these sleep-promoting effects were weakened in the LH^orexin and PVH^CRH neuron ablation groups, and disappeared in the orexin and CRH double-ablation group. Decreased c-Fos protein expression in the LH and PVH confirmed that Rg1 promoted NREM sleep by inhibiting orexin and CRH neurons. CONCLUSION Rg1 increases the duration of NREM sleep, underscoring the essential roles of LH^orexin and PVH^CRH neurons in facilitating the sleep-promoting effects of Rg1. Please cite this article as: Wang YY, Wu Y, Yu KW, Xie HY, Gui Y, Chen CR, Wang NH. Ginsenoside Rg1 promotes non-rapid eye movement sleep via inhibition of orexin neurons of the lateral hypothalamus and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus. J Integr Med. 2024; 22(6): 721-730.
Animals ; Ginsenosides/pharmacology* ; Orexins/metabolism* ; Mice, Inbred C57BL ; Neurons/metabolism* ; Paraventricular Hypothalamic Nucleus/metabolism* ; Male ; Hypothalamic Area, Lateral/metabolism* ; Corticotropin-Releasing Hormone/metabolism* ; Mice ; Sleep/drug effects*

The neuropeptide orexin is widely distributed in the nervous system. Previous studies showed that orexin is involved in the feeding behavior regulation by binding to its receptor 1 (OX1R) and receptor 2 (OX2R) to activate the downstream signaling pathway. Recent studies have demonstrated that the system of orexin and its receptors are also involved in important physiological processes such as sleep-wake, learning and memory, and pathological processes of various neurological diseases. In this review, we summarized the research progress on the function of the orexin and its receptor system in physiological and pathological processes, and revealed the correlation between orexin and nervous system diseases, in order to provide the theoretical guidance for the diagnosis and treatment of the related diseases in the future.
Humans ; Nervous System Diseases ; physiopathology ; Orexin Receptors ; physiology ; Orexins ; physiology ; Signal Transduction

Suvorexant, an orexin receptor antagonist used for insomnia, has been shown to have a preventive effect on delirium in a randomized placebo-controlled trial. However, its effectiveness in the management of nocturnal delirium has not yet been determined. Here we report four cases in which elderly patients with moderate to severe Alzheimer's disease who developed nocturnal delirium were treated with suvorexant. In case 1, 15 mg suvorexant was initiated to manage nocturnal delirium refractory to antipsychotics, antidepressants, and a Japanese herbal medicine, resulting in immediate sleep improvement. However, treatment discontinuation led to recurrence of symptoms, which were reversed by recommencing suvorexant. In case 2, as antipsychotics used for the treatment of nocturnal delirium were ineffective, 15 mg suvorexant was administered. The patient achieved rapid improvement in sleep. In case 3, the use of atypical antipsychotics for the treatment of nocturnal delirium was contraindicated, as the patient had diabetes. Therefore, 15 mg suvorexant was administered following good outcomes in cases 1 and 2, resulting in immediate sleep improvement. Finally, in case 4, 15 mg suvorexant was used as an initial medication for nocturnal delirium, and the patient showed sleep improvement immediately. Elevated orexin levels in the cerebrospinal fluid are reportedly linked to sleep deterioration in patients with moderate to severe Alzheimer's disease. The immediate and reproducible action and effectiveness of suvorexant observed in our patients suggest that enhanced cerebral orexin activity might be associated with sleep-wake cycle disturbances due to delirium in elderly patients with Alzheimer's disease.
Aged ; Alzheimer Disease ; Antidepressive Agents ; Antipsychotic Agents ; Asian Continental Ancestry Group ; Cerebrospinal Fluid ; Delirium ; Herbal Medicine ; Humans ; Orexins ; Recurrence ; Sleep Initiation and Maintenance Disorders

Alcoholism ; metabolism ; pathology ; Animals ; Humans ; Orexins ; metabolism

BACKGROUND: The trigeminal nucleus caudalis (Vc) is a primary central site for trigeminal transmitting. Noxious stimulation of the trigeminal nociceptors alters the central synaptic releases and neural expression of some inflammatory and trophic agents. Orexin-A and the orexin 1 receptor (OX1R) are expressed in pain pathways including trigeminal pain transmission. However, the the mechanism(s) underling orexin-A effects on trigeminal pain modulation have not been fully clarified. METHODS: Trigeminal pain was induced by subcutaneous injection of capsaicin in the upper lip in rats. The effect of trigeminal pain on cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) expression in the Vc of animals was determined by immunofluorescence. Subsequently, OX1R agonist (orexin-A) and antagonist (SB-334867-A) was administrated in the Vc to investigate the possible roles of the Vc OX1R on changes in COX-2 and BDNF levels following pain induction. RESULTS: The data indicated an increase in COX-2 and decrease in BDNF immuno-reactivity in the Vc of capsaicin, and capsaicin- pretreated with SB-334867-A (80 nM), groups of rat. However, the effect of capsaicin on COX-2 and BDNF expressions was reversed by a Vc microinjection of orexin-A (100 pM). CONCLUSIONS: Overall, the present data reveals that orexin-A can attenuate capsaicin-induced trigeminal pain through the modulation of pain effects on COX-2 and BDNF expressions in the Vc of rats.
Animals ; Brain-Derived Neurotrophic Factor ; Capsaicin ; Cyclooxygenase 2 ; Facial Pain ; Fluorescent Antibody Technique ; Injections, Subcutaneous ; Lip ; Microinjections ; Nociceptors ; Orexin Receptor Antagonists ; Orexins ; Pain Measurement ; Pain Perception ; Rats ; Trigeminal Caudal Nucleus ; Trigeminal Neuralgia ; Trigeminal Nuclei

OBJECTIVE: To compare the effect on post-stroke insomnia between the repetitive transcranial acupuncture stimulation (rTAS) and the conventional western medication in the patients and to explore the mechanism. METHODS: Ninety patients of post-stroke insomnia were randomized into a rTAS group, a medication group and a placebo group, 30 cases in each one. In the rTAS group, patients were intervened by rTAS. The acupoints were Baihui (GV 20), Ningshen (Extra), emotion area, Wangu (GB 12), Taiyang (EX-HN 5), Neiguan (PC 6), Shenmen (HT 7), Sanyinjiao (SP 6), Zhaohai (KI 6), Zusanli (ST 36) and Taichong (LR 3). Fast twist with small amplitude was used at Baihui (GV 20) and emotion area for 2-3 min, 200-300 r/min, once 15 min. Electroacupuncture (EA) was applied at Baihui (GV 20) and Ningshen (Extra), bilateral Wangu (GB 12), Sanyinjiao (SP 6) and Zhaohai (KI 6) on the same side, 10 Hz, 0.5-1 mA. The treatment was given for 40 min in the rTAS group, once a day. Diazepam was prescribed orally in the medication group before sleep, 2.5 mg a day. Starch capsule was used in the placebo group before sleep, once a day. All the treatment was given for continuous 1 month. The level of serum orexin A was observed before and after treatment. The effects were compared. The recurrence rate was recorded 3 months after treatment. RESULTS: The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 90.0% (27/30) repectively after treatment, which were better than 20.0% (6/30) in the placebo group (both <0.01). After treatment, the levels of serum orexin A in the rTAS group and the medication group were lower than those before treatment (both <0.01), which were lower than that in the placebo group after treatment (both <0.01), without statistical significance between the rTAS group and the medication group after treatment (>0.05). The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 86.7% (26/30) at follow-up repectively, which were better than 16.7% (5/30) in the placebo group (both <0.01). CONCLUSION The rTAS is safe and effective for post-stroke insomnia, which is similar to oral medication of diazepam. The decreasing serum orexin A may be one of the mechanisms.
Acupuncture Therapy ; Humans ; Orexins ; Sleep Initiation and Maintenance Disorders ; therapy ; Stroke

The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.
Animals ; Benzoxazoles ; pharmacology ; Diet, High-Fat ; Eating ; drug effects ; Fourth Ventricle ; Motor Activity ; drug effects ; Obesity ; Orexin Receptor Antagonists ; pharmacology ; Orexin Receptors ; Orexins ; pharmacology ; Rats ; Urea ; analogs & derivatives ; pharmacology

Although bipolar disorder is highly heritable, the identification of specific genetic variations is limited because of the complex traits underlying the disorder. We performed a genome-wide association study of bipolar disorder using a subphenotype that shows hypersomnia symptom during a major depressive episode. We investigated a total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples obtained from the Translational Genomics Institute and the Genetic Association Information Network. The gene emerging as the most significant by statistical analysis was rs1553441 (odds ratio=0.4093; p=1.20x10-5; Permuted p=6.0x10-6). However, the 5x0-8 threshold for statistical significance required in a genome-wide association study was not achieved. The functional enrichment pathway analysis showed significant enrichments in the adhesion, development-related, synaptic transmission-related, and cell recognition-related pathways. For further evaluation, each gene of the enriched pathways was reviewed and matched with genes that were suggested to be associated with psychiatric disorders by previous genetic studies. We found that the cadherin 13 and hypocretin (orexin) receptor 2 genes may be involved in the hypersomnia symptom during a major depressive episode of bipolar disorder.
Bipolar Disorder* ; Disorders of Excessive Somnolence* ; Genetic Variation ; Genome-Wide Association Study ; Genomics ; Information Services ; Polymorphism, Single Nucleotide ; Orexins