Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT<sub>2</sub>Melatonin Receptor Ligand

Ochoa‐Sanchez, Rafael; Comai, Stefano; Lacoste, Baptiste; Bambico, Francis Rodriguez; Domínguez-López, Sergio; Spadoni, Gilberto; Rivara, Silvia; Bedini, Annalida; Angeloni, Debora; Fraschini, F.; Mor, Marco; Tarzia, Giorgio; Descarries, Laurent; Gobbi, Gabriella

doi:10.1523/jneurosci.2676-11.2011

Cited by 110 publications

(133 citation statements)

References 51 publications

(56 reference statements)

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“…Selective MT2 receptor agonists increase NREMS duration compared to melatonin and non-selective MT1/MT2 agonists [17]. MT1 receptor knockout mice exhibited a significant increase in NREMS during the active/dark phase [18], whereas MT2 receptor knockout mice showed decreased NREMS duration [18]. Taken together, these knockout studies seem to suggest that MT1 and MT2 receptors modulate NREMS in an opposite manner [16].…”

Section: Effect Of Melatonin On Insomniamentioning

confidence: 88%

A review of sleep disorders and melatonin

Xie

Chen

et al. 2017

Neurological Research

279

181

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Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short-or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects.

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Section: Effect Of Melatonin On Insomniamentioning

confidence: 88%

A review of sleep disorders and melatonin

Xie

Chen

et al. 2017

Neurological Research

279

181

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“…31 Recently, using polyclonal antibodies 32 we have pointed out the presence of MT 2 receptors in the reticular thalamus, substantia nigra (pars reticulata), supraoptic nucleus, red nucleus and CA 2 and CA 3 areas of the hippocampus. 33 Using in situ hybridization histochemistry with selective and specific digoxigenin-labelled antisense and sense oligonucleotide probes, a robust hybridization of MT 1 and MT 2 receptor mRNA has been observed in the SCN. 34 In humans, MT 2 receptors have been recently localized at the level of the SCN, the supraoptic nucleus and the paraventricular nucleus using polyclonal specific antibodies.…”

Section: Where Are They?mentioning

confidence: 99%

“…1). Importantly, while UCM765 is an MT 2 partial agonist (α = 0.6) that possesses 100-fold higher affinity for MT 2 than MT 1 receptors, 33,44 IIK7 is an MT 2 full agonist with 90-fold higher affinity for MT 2 than MT 1 receptors. 49 Even though experiments comparing the sleep-promoting properties of the 2 compounds have not yet been conducted, it is important to remember that partial agonists, thanks to their "flexible" properties compared with full agonists, are becoming more and more popular in psychopharmacology.…”

Section: What Are Their Roles?mentioning

confidence: 99%

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Comai

Gobbi

2014

J Psychiatry Neurosci

149

126

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IntroductionMelatonin (MLT) is a neurohormone synthesized from serotonin (5-HT) and secreted foremost by the mammalian pineal gland following a distinct circadian rhythm with the acrophase during the dark phase and the nadir during the light phase in both diurnal and nocturnal species.1 A typical human adult's average daytime and nighttime levels of blood MLT are approximately 10 pg/mL and 60 pg/mL, respectively.2 Its production is controlled through the suprachiasmatic nucleus (SCN) by the photoperiod, peaking at night and dropping during the day. Melatonin is involved in numerous physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses and cardiac functions. 3,4 Most of the effects of MLT in the brain result from the activation of 2 high-affinity G-protein coupled receptors (GPCRs), MT 1 and MT 2 .5 Of note, GPCRs have a proven history of being excellent therapeutic targets. Recent market analyses indicate that 40%-50% of modern drugs and almost 25% of the top 200 best-selling drugs target GPCRs. 6 In addition to these high-affinity MLT receptors, another low-affinity MLT binding site, MT 3 , has recently been characterized as an MLT-sensitive form of the human enzyme quinone reductase 2. 7 The functional characterization of MT 1 and MT 2 receptors in target tissues is hampered by the paucity of selective MT 1 and MT 2 receptor ligands. Structural Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT 1 (MEL1a) and MT 2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT 1 and MT 2 receptors. Here we have reviewed current knowledge about the implications of MT 2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT 2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT 2 receptor. Results: These studies demonstrate that MT 2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT 2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT 2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT 2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, M...

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“…Besides its role in consciousness and sleep, this nucleus serves as an ''attentional gate'' for sensory information [45]. The reticular nucleus is thus a promising area in which to explore analgesic effects and may be a target for novel drugs [45][46][47].…”

Section: Increased Tspo Expression Mediated the Up-regulation Of Neurmentioning

confidence: 99%

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

et al. 2016

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Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of c-aminobutyric acid A receptors (GABA A Rs), which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-performance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids (pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone) in the chronic stage of neuropathic pain (28 days after spared nerve injury) in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus (AP -3.0 mm, ML ±3.0 mm, DV 6.0 mm) alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were significantly attenuated by the GABA A R antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

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Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT₂Melatonin Receptor Ligand

Abstract: Melatonin activates two brain G-protein coupled receptors, MT

Cited by 110 publications

References 51 publications

A review of sleep disorders and melatonin

A review of sleep disorders and melatonin

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

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Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT2Melatonin Receptor Ligand

Abstract: Melatonin activates two brain G-protein coupled receptors, MT

Cited by 110 publications

References 51 publications

A review of sleep disorders and melatonin

A review of sleep disorders and melatonin

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

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Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT₂Melatonin Receptor Ligand