Understanding sleep-wake mechanisms and drug discovery

ABSTRACT

Introduction: Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use.

Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy.

Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.

KEYWORDS:

• Chronic insomnia
• histamine inverse agonist
• hypocretin
• narcolepsy
• orexin agonists
• orexin antagonists
• sleep disorders
• sleep-wake cycle
• melatonin
• melanin concentrating hormone

Article highlights

• Sleep disorders are a widespread problem with great economic and social repercussions

• Sleep is a highly regulated behavior initiated through a complex interaction of different levels of phenomena (genetic, environmental, hormonal and neurotransmission, to cite some).

• Therapeutic approaches for sleep disorders have many shortcomings including harsh side-effect profiles, tolerance and next-day impairment.

• The orexinergic system is the newest target for drug development for sleep disorders

• The melanin-concentrating hormone system in the near future might become the target of a new generation of sleep medication.

This box summarizes key points contained in the article.

Acknowledgments

We thank Marcela Palomero-Rivero and Diana Millán-Aldaco for their critical comments and Francisco Pérez-Eugenio and Ariadna Aparicio Juárez for their technical assistance.

Declaration of interest

AC Equihua-Benitez has received a fellowship (No. 346052) from the Consejo Nacional de Cienca y Tecnologia (CONACYT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the Dirección General de Asuntos del Personal Académico, Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica, Universidad Nacional Autónoma de México (DGAPA-PAPIIT) via grants IN207116 and IN204715.