Chronic fatigue syndrome is a heterogeneous disorder with unknown pathogenesis and etiology, characterized by disabling fatigue, difficulty in concentration and memory, and concomitant skeletal and muscular pain. Several mechanisms have been suggested to play a role in CFS[1], such as excessive oxidative stress following exertion, immune imbalance characterized by decreased natural killer cell and macrophage activity, immunoglobulin G subclass deficiencies (IgG-1[2], IgG-3) and decreased serum concentrations of complement component. Autoantibodies were also suggested as a possible factor in the pathogenesis of CFS. Recent studies indicate that anti-serotonin, anti-microtubule-associated protein 2 and anti-muscarinic cholinergic receptor 1 may play a role in the pathogenesis of CFS. It has been demonstrated that impairment in vasoactive neuropeptide metabolism may explain the CFS symptoms

The novel neuropeptides hypocretin/orexin have recently been located on the lateral hypothalamus cells. This system has been linked to the regulation of both feeding and sleep, and recent studies have found an association between a defect in these neuropeptides and narcolepsy. We conducted a MED­LINE review of all the articles published since the discovery of hypocretin/orexin peptides, narrowing the field to the relation­ship between these neuropeptides and sleep. The finding of a deletion in the transcription of the hypocretin receptor 2 gene in narcoleptic Doberman pinschers and the development of a knockout of the hypocretin gene in mice pointed to the relevance of this system in the sleep-wake cycle. We provide further evidence of the role of the hypocretin/orexin system in narcolepsy and in sleep regulation and present an integrative model of the pathophysiology of narcolepsy. The discovery of the link between these peptides and narcolepsy opens new avenues to both the understanding of sleep mechanisms and therapeutic implications for sleep disorders.