Neuropeptides as possible targets in sleep disorders.

Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.