**1. Introduction**

Sleep is fundamental to the mental and physical health of a person. Lack of sleep is a significant risk factor for obesity, diabetes, diseases of the cardiovascular system, as well as anxiety and depressive disorders. Sleep disorders have a significant financial burden on the healthcare system and complicate the treatment of major somatic diseases. Sleep disorders are a category of diseases that include hypersomnia, insomnia (accompanied by difficulty falling asleep, maintaining sleep, and early awakening), circadian rhythm disturbance, parasomnia, and sleepdependent breathing disorders. The consequence of some sleep disorders is a violation of falling asleep and maintaining sleep, drowsiness, and, as a consequence, a decrease in the quality of life. Some sleep disorders can also lead to severe impaired ability to perform every day and professional tasks related to concentration, switching attention, and spatial perception [1].

The development of pharmacological treatment methods has provoked an increase in the frequency of sleep disorders in the last decade, as a result of undesirable effects of this therapy. The most common disease is insomnia, which according to the classification criteria for mental disorders *Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV)* in the general population is found in 4–6%.

The main classes of drugs for the treatment of insomnia are barbiturates, benzodiazepines, benzodiazepine agonists, antidepressants, and anxiolytics. These drugs can cause a large number of side effects associated with excessive daytime sleepiness, decreased concentration, and switching attention and can cause deterioration of short-term memory. In some cases, with prolonged use of these drugs, dependence may form, and with cancelation, a "rebound phenomenon" may occur. In this regard, it becomes relevant to search for new pharmaceuticals that reduce the number and severity of these side effects while maintaining the proper level of effectiveness. One of these drugs, with long-term administration of minimal side effects and sufficient effectiveness in certain sleep disorders, is melatonin. Melatonin is mainly produced by the pineal gland with a peak of activity at night; the concentration fluctuation coincides with the circadian rhythm. Melatonin-based preparations have good tolerance in various age periods, without forming dependency [2–4].

Other effects are inherent to melatonin, namely, regulation of circadian, seasonal rhythms; regulation of the psychoemotional and cognitive sphere; antioxidant, neuroprotective, and geroprotective effect; immunomodulatory; vegetative stabilizing; and oncological and stress-protective effect.

The multiplicity of effects of melatonin is due to the large number of targets on which this hormone has an effect. The most studied mechanism for the implementation of the action of melatonin remains its effect on suprachiasmal nuclei (SCN) of the hypothalamus. Through SCN, the chronobiological effect of melatonin is realized and, of course, its hypnotic effects. Melatonin interacts with two types of G-protein-bound receptors—MT1 and MT2 [5]. MT1-type receptors are distributed in the hippocampus, caudate nucleus, pillow, suprachiasmatic nuclei, paraventricular nucleus, supraoptic nucleus, Meynert nucleus, adjacent nucleus, substantia nigra, mammary bodies, and retina. MT2-type receptors are mainly detected in the hippocampus, SCN, and the retina. Both types of receptors are expressed by neurons and glial cells of the cerebral and cerebellar cortex, in the thalamus, and pineal gland [5, 6].

Melatonin is released into the blood plasma as a rhythmic oscillatory pattern, which is regulated by SCN neurons. Daylight suppresses the release of melatonin through the retinohypothalamic tract, projecting from melanopsin-expressing retinal ganglion cells to SCN neurons. It is known, for example, that night illumination is 2000–2500 Lux within 2 hours, which completely inhibits the secretion of melatonin. On the other hand, traditional home light (50–300 Lux) practically does not have a suppressive effect on the secretion of melatonin [7]. The neural relationship between the structures of the central nervous system, where axons of melanopsin-expressing ganglion cells are projected, primarily with SCN neurons and the sympathetic nervous system, is via the superior cervical sympathetic ganglion, from where the nerve fibers go directly to the pinealocytes and regulate the exocytosis of norepinephrine, which activates melatonin synthesis and its release [8]. As mentioned above, melatonin easily penetrates through biological barrier: it is secreted continuously into the blood plasma and enters various fluids (saliva, urine, cerebrospinal fluid, preovulatory follicle, spermatozoa, amniotic fluid, and human milk). The maximum level of melatonin in blood plasma is at 03.00–04.00 at night. The indicator varies depending on the chronotype and is not determined in the daytime. Melatonin levels have a pronounced intersubject heterogeneity but are steadily repeated in the same person. After birth, the rhythmic production of melatonin during the day reaches very high levels by 3–6 years of life and then decreases by almost 80% to levels in an adult. The melatonin rhythm is generated by the endogenous clock of the hypothalamic SCN neurons, which are affected by the light/dark cycle (zeitgeber). Seasonal effects on the secretion of melatonin are manifested in an increase in nighttime secretion of melatonin, which is associated

**21**

disturbances.

*Clinical Use of Melatonin in the Treatment of Sleep Disorders*

depressive episodes during a short photoperiod.

with a decrease in plasma of ovarian steroids. On the other hand, urban lighting reduces seasonal differences in the secretion of melatonin, cortisol, and thyrotropin. Winter-type seasonal affective disorders are characterized by recurrent

Melatonin, due to its amphotericity (amphiphilicity), is able to penetrate into the cell, organelles, and nuclear membranes and directly interacts with intracellular molecules, exerting a non–receptor-mediated effect. Along with this, melatonin exerts a receptor-mediated effect on target cells, as a result of the interaction of the hormone with either membrane or nuclear receptors [9]. The main physiological functions of melatonin are due to its hormonal properties; however, the hormone also has an autocrine and paracrine effect, in particular in the retina and gastroin-

Outside of SCN, MT1 and MT2 receptors are also found in large numbers in the duodenum, colon, cecum and appendix, gallbladder epithelium, parotid gland, pancreas, β-cells of the endocrine system, pancreas, coronary, and cerebral arteries adipose tissue. In addition to membrane receptors for melatonin, there are also nuclear receptors: RORα and RORβ. The prevalence of RORα is highest in T and B lymphocytes, neutrophils, and monocytes, whereas RORβ are found mainly in the

The modulating effect on sleep architecture is also realized by melatonin due to membrane receptors MT1 and MT2. The activation of the MT2 receptor contributes to increasing the duration of slow-wave sleep. The activation of the MT 1 receptor

The effects of melatonin, in addition to effects on SCN, on neural networks of passive brain function default mode network (DMN) were also demonstrated. Their activation is accompanied by the appearance of a feeling of fatigue and is characterized by changes typical of sleep in such parts of the cortex as the precuneus located in the rostromedial aspect of the occipital cortex [13, 14]. Because the general effect of melatonin through two membrane receptors does not increase the duration of slow-wave sleep (SWS) [15], the main effect of melatonin is not associated with its homeostatic effect on sleep. Therefore, its effect can be attributed to sleep regula-

The multiple representation of melatonin receptors in the central nervous system, its effect on one of the key components of the regulation of the sleep-wake cycle, leads to the multiplicity of the clinical use of this hormone, especially in pathological conditions accompanied by primary or secondary circadian rhythm

Circadian disturbances of the sleep-wake rhythm are associated with disconnection of the synchronization of the endogenous circadian rhythm and environmental influences. Melatonin signals the onset of darkness, and activation of its production indirectly depends on the activity of intrinsically photosensitive retinal ganglion cells (ipRGC) or true light-sensitive retinal ganglion cells. However, there is also an endogenous melatonin release profile that allows SCN activation regardless of external light, maintaining sleep-wake rhythms and neuroendocrine rhythms in a 24-hour cycle. However, the absence of external-stabilizing effect of zeitgeber (daily light change) can lead to the formation of a non-24-hour sleep-wake cycle. For example, in completely blind subjects, it is quite common (in 50–75% of cases)

*DOI: http://dx.doi.org/10.5772/intechopen.92656*

brain, pineal gland, retina, and spleen.

tion through the circadian component [16].

**2. Melatonin and sleep disorders**

**2.1 Melatonin and disorders of the sleep-wake cycle**

has a decrease in the duration of slow-wave sleep [11, 12].

testinal tract [10].

#### *Clinical Use of Melatonin in the Treatment of Sleep Disorders DOI: http://dx.doi.org/10.5772/intechopen.92656*

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

good tolerance in various age periods, without forming dependency [2–4].

stabilizing; and oncological and stress-protective effect.

Other effects are inherent to melatonin, namely, regulation of circadian, seasonal rhythms; regulation of the psychoemotional and cognitive sphere; antioxidant, neuroprotective, and geroprotective effect; immunomodulatory; vegetative

The multiplicity of effects of melatonin is due to the large number of targets on which this hormone has an effect. The most studied mechanism for the implementation of the action of melatonin remains its effect on suprachiasmal nuclei (SCN) of the hypothalamus. Through SCN, the chronobiological effect of melatonin is realized and, of course, its hypnotic effects. Melatonin interacts with two types of G-protein-bound receptors—MT1 and MT2 [5]. MT1-type receptors are distributed in the hippocampus, caudate nucleus, pillow, suprachiasmatic nuclei, paraventricular nucleus, supraoptic nucleus, Meynert nucleus, adjacent nucleus, substantia nigra, mammary bodies, and retina. MT2-type receptors are mainly detected in the hippocampus, SCN, and the retina. Both types of receptors are expressed by neurons and glial cells of the cerebral and cerebellar cortex, in the thalamus, and

Melatonin is released into the blood plasma as a rhythmic oscillatory pattern, which is regulated by SCN neurons. Daylight suppresses the release of melatonin through the retinohypothalamic tract, projecting from melanopsin-expressing retinal ganglion cells to SCN neurons. It is known, for example, that night illumination is 2000–2500 Lux within 2 hours, which completely inhibits the secretion of melatonin. On the other hand, traditional home light (50–300 Lux) practically does not have a suppressive effect on the secretion of melatonin [7]. The neural relationship between the structures of the central nervous system, where axons of melanopsin-expressing ganglion cells are projected, primarily with SCN neurons and the sympathetic nervous system, is via the superior cervical sympathetic ganglion, from where the nerve fibers go directly to the pinealocytes and regulate the exocytosis of norepinephrine, which activates melatonin synthesis and its release [8]. As mentioned above, melatonin easily penetrates through biological barrier: it is secreted continuously into the blood plasma and enters various fluids (saliva, urine, cerebrospinal fluid, preovulatory follicle, spermatozoa, amniotic fluid, and human milk). The maximum level of melatonin in blood plasma is at 03.00–04.00 at night. The indicator varies depending on the chronotype and is not determined in the daytime. Melatonin levels have a pronounced intersubject heterogeneity but are steadily repeated in the same person. After birth, the rhythmic production of melatonin during the day reaches very high levels by 3–6 years of life and then decreases by almost 80% to levels in an adult. The melatonin rhythm is generated by the endogenous clock of the hypothalamic SCN neurons, which are affected by the light/dark cycle (zeitgeber). Seasonal effects on the secretion of melatonin are manifested in an increase in nighttime secretion of melatonin, which is associated

The main classes of drugs for the treatment of insomnia are barbiturates, benzodiazepines, benzodiazepine agonists, antidepressants, and anxiolytics. These drugs can cause a large number of side effects associated with excessive daytime sleepiness, decreased concentration, and switching attention and can cause deterioration of short-term memory. In some cases, with prolonged use of these drugs, dependence may form, and with cancelation, a "rebound phenomenon" may occur. In this regard, it becomes relevant to search for new pharmaceuticals that reduce the number and severity of these side effects while maintaining the proper level of effectiveness. One of these drugs, with long-term administration of minimal side effects and sufficient effectiveness in certain sleep disorders, is melatonin. Melatonin is mainly produced by the pineal gland with a peak of activity at night; the concentration fluctuation coincides with the circadian rhythm. Melatonin-based preparations have

**20**

pineal gland [5, 6].

with a decrease in plasma of ovarian steroids. On the other hand, urban lighting reduces seasonal differences in the secretion of melatonin, cortisol, and thyrotropin. Winter-type seasonal affective disorders are characterized by recurrent depressive episodes during a short photoperiod.

Melatonin, due to its amphotericity (amphiphilicity), is able to penetrate into the cell, organelles, and nuclear membranes and directly interacts with intracellular molecules, exerting a non–receptor-mediated effect. Along with this, melatonin exerts a receptor-mediated effect on target cells, as a result of the interaction of the hormone with either membrane or nuclear receptors [9]. The main physiological functions of melatonin are due to its hormonal properties; however, the hormone also has an autocrine and paracrine effect, in particular in the retina and gastrointestinal tract [10].

Outside of SCN, MT1 and MT2 receptors are also found in large numbers in the duodenum, colon, cecum and appendix, gallbladder epithelium, parotid gland, pancreas, β-cells of the endocrine system, pancreas, coronary, and cerebral arteries adipose tissue. In addition to membrane receptors for melatonin, there are also nuclear receptors: RORα and RORβ. The prevalence of RORα is highest in T and B lymphocytes, neutrophils, and monocytes, whereas RORβ are found mainly in the brain, pineal gland, retina, and spleen.

The modulating effect on sleep architecture is also realized by melatonin due to membrane receptors MT1 and MT2. The activation of the MT2 receptor contributes to increasing the duration of slow-wave sleep. The activation of the MT 1 receptor has a decrease in the duration of slow-wave sleep [11, 12].

The effects of melatonin, in addition to effects on SCN, on neural networks of passive brain function default mode network (DMN) were also demonstrated. Their activation is accompanied by the appearance of a feeling of fatigue and is characterized by changes typical of sleep in such parts of the cortex as the precuneus located in the rostromedial aspect of the occipital cortex [13, 14]. Because the general effect of melatonin through two membrane receptors does not increase the duration of slow-wave sleep (SWS) [15], the main effect of melatonin is not associated with its homeostatic effect on sleep. Therefore, its effect can be attributed to sleep regulation through the circadian component [16].

The multiple representation of melatonin receptors in the central nervous system, its effect on one of the key components of the regulation of the sleep-wake cycle, leads to the multiplicity of the clinical use of this hormone, especially in pathological conditions accompanied by primary or secondary circadian rhythm disturbances.
