Hypothalamic neuropeptides regulating arousal, wakefulness, appetite, and stress. Orexin A (33 aa, disulfide bonds) and Orexin B (28 aa) derive from prepro-orexin and act at OX1R/OX2R (Orexin B more OX2R-selective). Key in sleep-wake cycles and energy balance.
Orexin A and Orexin B
Also known as: Hypocretins
Overview
Benefits
- Sleep regulation
- Appetite control
- Cognitive function
- Stress management
Consider This Peptide If You Want To
- Enhance wakefulness, focus, and mental clarity
- Regulate sleep-wake cycles and energy balance
Dosage & Administration
Dosage Guidelines
Recommended Dosage
• Amount:100 mcg
• Frequency:daily
• Duration:4 weeks
• Rest Period:
• Time of Day:morning
• Ingestion:intranasal
Administration Routes:Intranasal
Research Findings on Dosage:
Intranasal Spray:
• Commonly Reported Dosage: 100-150 mcg once daily in the morning
• Duration: as needed
Mechanism of Action
Mechanism of Action
How this peptide works in the body
Sleep-Wake Regulation:
Orexins activate OX1R and OX2R in the lateral hypothalamus, exciting wake-promoting neurons in the tuberomammillary nucleus (TMN), locus coeruleus (LC), and raphe nuclei. This enhances histaminergic (TMN), noradrenergic (LC), and serotonergic (raphe nuclei) signaling, reinforcing wakefulness while inhibiting GABAergic neurons in the ventrolateral preoptic nucleus (VLPO) to suppress sleep initiation.
Appetite Control:
Orexins stimulate feeding by activating the lateral hypothalamus (LH) and enhancing dopaminergic signaling in the ventral tegmental area (VTA), increasing motivation for food intake. They also act on neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons in the arcuate nucleus to promote hunger while inhibiting pro-opiomelanocortin (POMC) neurons, which suppress appetite.
Stress and Energy Homeostasis:
Orexins engage the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), leading to increased ACTH and cortisol secretion for heightened stress response. They also regulate brown adipose tissue (BAT) thermogenesis by activating sympathetic nervous system (SNS) pathways, increasing uncoupling protein 1 (UCP1) expression, and boosting energy expenditure.
Neurotransmitter Modulation:
Orexins enhance synaptic activity by increasing intracellular calcium (Ca²⁺) influx through phospholipase C (PLC) and inositol trisphosphate (IP3) pathways, amplifying excitatory post-synaptic potentials (EPSPs). They also facilitate AMPA and NMDA receptor phosphorylation, modulate dopamine (D1 receptors in the nucleus accumbens), norepinephrine, acetylcholine, and serotonin systems, and fine-tune cognitive function, mood, and arousal.
Consider Stacking With
- Melatonin receptor agonists
Side Effects & Cautions
Common Side Effects
- Headache
Rare Side Effects
- Insomnia (rare)
Research & References
Research Highlights
Narcolepsy and Orexin Deficiency:
Research confirms orexin knockout mice exhibit excessive daytime sleepiness and disrupted REM sleep patterns.
Feeding and Reward Pathways:
Studies reveal orexins' role in enhancing dopamine release, linking food intake with reward systems.
Stress Response Modulation:
Orexins activate the HPA axis, influencing cortisol secretion and behavioral adaptation to stress.
Energy Expenditure:
Findings indicate orexins regulate thermogenesis through brown adipose tissue activation.
References
Sakurai, T., et al. (1998). "Orexins and their receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior." Cell, 92(4), 573-585
Rodgers, R. J., et al. (2002). "Orexin actions on energy balance and feeding behavior." Neuropharmacology, 42(8), 1308-1316
Schwartz, M. W., et al. (1998). "Role of orexins in energy homeostasis." Nature Medicine, 4(4), 385-389
van den Pol, A. N., et al. (1998). "Hypothalamic stimulation of wakefulness and energy expenditure by orexins." Nature Neuroscience, 1(8), 611-613