Insomnia or insufficient sleep is a common malady, affecting millions of people worldwide. Mammalian sleep normally progresses from wakefulness to non-rapid eye movement sleep (NREMS) before transitioning to rapid eye movement sleep (REMS). NREMS is also called slow-wave, deep or restorative sleep because important functions such as memory consolidation and metabolic regulation occur during this phase. Existing pharmacologic treatments for insomnia, such as benzodiazepines, disrupt natural sleep progression and may result in cognitive dysfunction as well as dependence and abuse. Therefore, the development of new therapies that selectively increase NREMS without disrupting sleep progression has remained a clinical goal.

Melatonin, nicknamed the 'sleep hormone', is produced by the pineal gland in the absence of light stimulation and is involved in regulating sleep and circadian rhythms, as well as in depression and anxiety. Its effects on sleep in humans and in animals have been studied, but results have been inconclusive.

Melatonin acts via two receptors in the brain, MT1 and MT2, whose individual effects on sleep have yet to be defined. Newly published work from Gabriella Gobbi and colleagues (McGill University and McGill University Health Center, Montreal, Quebec, Canada) in collaboration with chemists from Carlo Bo University of Urbino and University of Parma in Italy now shows that the two receptors have opposing effects on sleep in rodents. Gobbi told the Montreal Gazette, “It was tough because we went against conventional wisdom on melatonin. We thought both receptors would promote sleep and it's not true—the receptors have opposite roles.” MT1 and MT2 have conflicting roles in other systems as well: in the hippocampus, the two receptors differentially modulate GABA receptor function, and in the vascular system, MT1 acts as a constrictor whereas MT2 acts as a dilator.

The researchers used a new drug called UCM765 to selectively activate MT2 receptors. Administration of 40 mg UCM765 per kg body weight in rats decreased latency to sleep by 60%, decreased the amount of time spent awake by almost 40% and increased the duration of NREMS sleep by almost 50%, without affecting REMS (J. Neurosci. 31, 18439–18452; 2011). These effects of UCM765 on NREMS were absent when MT2 receptors were genetically or pharmacologically inactivated.

Gobbi's results showed that in rodents, activation of the MT2 receptor specifically promoted NREMS without altering sleep progression. “Specifying the role of MT2 receptors... represent[s] a major scientific breakthrough that may designate them as a promising novel target for future treatments of insomnia,” Gobbi stated in a press release.