10) Some types of human narcolepsy have been associated with a loss of orexin activity and reduced orexin levels in the cerebrospinal fluid, further indicating that reduced orexin function in humans can produce decreased wakefulness and an increase in propensity to sleep. Similar effects have been observed in orexin 1 (OX1) KO, orexin 2 (OX2) KO, and dual OX1/OX2 KO mice. KO mice devoid of the orexin precursor prepro-orexin have exhibited a behavioral phenotype similar to human narcolepsy. 9Īdditional evidence for the role of orexin-A in the maintenance of wakefulness is provided by studies in knockout (KO) mice. 6 In addition to activating LC neurones, orexin-A was subsequently found to increase the neuronal firing of serotonergic raphe neurones 7 and of the histaminergic cells of the tuberomammillary nucleus, 8 both of which are postulated to play important roles in the maintenance of wakefulness. 5 Further studies using electroencephalography (EEG) and electromyography (EMG) recordings in rats demonstrated that the administration of orexin-A at the beginning of the normal sleep period increased the time spent awake and decreased both paradoxical (rapid eye movement, REM) and slow wave (deep) sleep. 4 Intracerebroventricular injection of orexin-A in rats was initially found to increase locus coeruleus (LC) firing as well as locomotor activity, and rearing and grooming behavior. 3 Although these treatments are effective, there is still need for improved drugs that can cover a broader population of patients with insomnia, i.e., patients with impaired sleep induction, impaired sleep maintenance, or both, and which do not have any of the limitations current treatments may have, such as next day residual symptoms, tolerance, dependence, restoration of a physiological sleep profile, and muscle relaxation.Ī large body of evidence supports the role of orexins (also known as hypocretins) in controlling arousal and sleep/wake states. 2 More recently, melatonin slow release has been approved for the treatment of a subset of patients with insomnia and ramelteon (a melatonin agonist) has been approved for the treatment of patients with impaired sleep induction. Until recently the only approved pharmacological treatments for insomnia were acting on the GABA system by either binding to the benzodiazepine ligand site of the GABA receptor or by modulating the GABA receptor directly. Behavioral therapy and pharmacotherapy are both used to treat patients with chronic insomnia. 1 Although, insomnia can be only transient, in most cases it tends to become chronic prompting patients to ask for treatment. Insomnia is the most prevalent sleep disorder epidemiologic studies show that prevalence of primary insomnia ranges from 1% to 2% of the population, but increases up to 22% of the population if one considers insomnia comorbid to other medical conditions.