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Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments. [ABSTRACT FROM AUTHOR]

The melatonin system and circadian disruption have well‐established links with aggressive behaviors; however, the biological underpinnings have not been thoroughly investigated. Here, we aimed at examining the current knowledge regarding the neurobiological and psychopharmacological involvement of the melatonin system in aggressive/violent behaviors. To this end, we performed a systematic review on Embase and Pubmed/MEDLINE of preclinical and clinical evidence linking the melatonin system, melatonin, and melatoninergic drugs with aggressive/violent behaviors. Two blinded raters performed an independent screening of the relevant literature. Overall, this review included 38 papers distributed between clinical and preclinical models. Eleven papers specifically addressed the existing evidence in rodent models, five in fish models, and 21 in humans. The data indicate that depending on the species, model, and timing of administration, melatonin may exert a complex influence on aggressive/violent behaviors. Particularly, the apparent contrasting findings on the link between the melatonin system and aggression/violence (with either increased, no, or decreased effect) shown in preclinical models underscore the need for further research to develop more accurate and fruitful translational models. Likewise, the significant heterogeneity found in the results of clinical studies does not allow yet to draw any firm conclusion on the efficacy of melatonin or melatonergic drugs on aggressive/violent behaviors. However, findings in children and in traits associated with aggressive/violent behavior, including irritability and anger, are emerging and deserve empirical attention given the low toxicity of melatonin and melatonergic drugs. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel‐running detection, we found that exogenous MLT could completely recover the period length prolonged by N‐methyl‐D‐aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK‐801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK‐801 decreased Ca2+‐related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in‐vivo to further monitor intracellular Ca2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca2+ fluorescence compared with MK‐801‐injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4‐phenyl‐2‐propionamidotetralin (4P‐PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK‐801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT2 receptor knockout (MT2−/−) mice show a decreased nonrapid eye movement sleep over 24 hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5‐HT) neurons and anxiety‐ and depression‐like behavior. We found that the 5‐HT burst‐firing activity was tonically reduced across the whole 24 hours in MT2−/− mice compared with MT2+/+ mice. Importantly, the physiological changes in the spontaneous firing activity of DRN 5‐HT neurons during the light/dark cycle were nullified in MT2−/− mice, with a higher DRN 5‐HT neural firing activity during the light phase in MT2−/− than in MT2+/+ mice. The role of MT2 receptors over DRN 5‐HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose dependently inhibited DRN 5‐HT activity, mostly during the dark phase. Compared with MT2+/+, MT2−/− mice displayed an anxiety‐like phenotype in the novelty‐suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark than during the light phase in MT2+/+ mice, the opposite was seen in MT2−/− mice. No differences between MT2+/+ and MT2−/− mice were observed for depression‐like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT2 receptor genetic inactivation impacts 5‐HT neurotransmission and interferes with anxiety levels by perturbing the physiologic light/dark pattern. [ABSTRACT FROM AUTHOR]

Melatonin (MLT), a neuromodulator mainly acting through two G-protein coupled receptors MT 1 and MT 2 , regulates many brain functions, including circadian rhythms, mood, pain and sleep. MLT and non-selective MT 1 /MT 2 receptor agonists are clinically used in neuropsychiatric and/or sleep disorders. However, the selective roles of the MT 1 and MT 2 receptors need to be clarified. Here, we review the role of the MT 1 receptor in neuropsychopharmacology, describe the anatomical localization of MT 1 receptors in the brain, discuss the medicinal chemistry, biochemistry and molecular aspects of the receptor, and explore the findings linking MT 1 receptors to psychiatric and neurological disorders. MT 1 receptors are localized in brain regions which regulate circadian rhythms, sleep, and mood, such as the suprachiasmatic nucleus, cortex, hippocampus, dorsal raphe nucleus and lateral hypothalamus. Their activation modulates intracellular signaling pathways also targeted by psychoactive drugs, including antidepressants and mood stabilizers. MT 1 receptor knockout mice display increased anxiety, a depressive-like phenotype, increased propensity to reward and addiction, and reduced Rapid-Eye-Movement sleep. These behavioral dysfunctions are associated with altered serotonergic and noradrenergic neurotransmissions. Several studies indicate that the MT 1 , rather than MT 2 , receptor is implicated in circadian rhythm regulation. The involvement of MT 1 receptors in Alzheimer's and Huntington diseases has also been proposed. Postmortem studies in depressed patients have further confirmed the possible involvement of MT 1 receptors in depression. Overall, there is substantial evidence indicating a role for MT 1 receptor in modulating brain function and mood. Consequently, this MLT receptor subtype deserves to be further examined as a novel target for neuropsychopharmacological drug development. [ABSTRACT FROM AUTHOR]

The pathophysiological function of the G-protein coupled melatonin MT1 and MT2 receptors has not yet been well-clarified. Recent advancements using selective MT1/ MT2 receptor ligands and MT1/MT2 receptor knockout mice have suggested that the activation of the MT1 receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT1 knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT1 receptors is also distinct from MT2 receptors; for example, MT2 receptors are located in the reticular thalamus (NREM area), while the MT1 receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT1-MT2 receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT1/MT2 non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT1 and MT2 receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT2 agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT1 agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT1 but not MT2 receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT1 and/or MT2 receptors as targets for neuropsychopharmacology drug development. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT 2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT 2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5–40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20 mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT 2 partial agonists were blocked by the pre-treatment with the MT 2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT 2 melatonin receptor may be a novel target for analgesic drug development. [ABSTRACT FROM AUTHOR]

Highlights: [•] Melatonin decreases the latency to NREM sleep. [•] Melatonin does not alter the duration of sleep during the 24-h light-dark cycle. [•] The non-selective MT1/MT2 receptor agonist UCM793 affects the number of episodes of wakefulness but not sleep. [•] MLT and the non-selective MT1/MT2 receptor agonist UCM793 differently influence quality of the three vigilance states. [•] Pharmacological activation of MT2 receptors increases NREMS. [ABSTRACT FROM AUTHOR]

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), MT1 (MEL1a) and MT2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT1 and MT2 receptors. Here we have reviewed current knowledge about the implications of MT2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT2 receptor. Results: These studies demonstrate that MT2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT2 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, MT2 receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available. [ABSTRACT FROM AUTHOR]

Abstract: The neurohormone melatonin activates two G-protein coupled receptors, MT1 and MT2. Melatonin is implicated in circadian rhythms and sleep regulation, but the role of its receptors remains to be defined. We have therefore characterized the spontaneous vigilance states in wild-type (WT) mice and in three different types of transgenic mice: mice with genetic inactivation of MT1 (MT1 −/−), MT2 (MT2 −/−) and both MT1/MT2 (MT1 −/−/MT2 −/−) receptors. Electroencephalographic (EEG) and electromyographic sleep–wake patterns were recorded across the 24-h light–dark cycle. MT1 −/−mice displayed a decrease (−37.3%) of the 24-h rapid eye movement sleep (REMS) time whereas MT2 −/−mice showed a decrease (−17.3%) of the 24-h non rapid eye movement sleep (NREMS) time and an increase in wakefulness time (14.8%). These differences were the result of changes occurring in particular during the light/inactive phase. Surprisingly, MT1 −/−/MT2 −/− mice showed only an increase (8.9%) of the time spent awake during the 24-h. These changes were correlated to a decrease of the REMS EEG theta power in MT1 −/−mice, of the NREMS EEG delta power in MT2 −/−mice, and an increase of the REMS and wakefulness EEG theta power in MT1 −/−/MT2 −/− mice. Our results show that the genetic inactivation of both MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 receptors, and reduced REMS induced by the lack of MT1 receptors. Therefore, each melatonin receptor subtype differently regulates the vigilance states: MT2 receptors mainly NREMS, whereas MT1 receptors REMS. [Copyright &y& Elsevier]

Melatonin activates two brain G-protein coupled receptors, MT1 and MT2 , whose differential roles in the sleep-wake cycle remain to be defined. The novel MT2 receptor partial agonist, N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement ofNREMSby UCM765 is nullified by the pharmacological blockade or genetic deletion of MT2 receptors.MT2 , but not MT1 , knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT2 receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT2 antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT2 receptors may represent a novel target for the treatment of sleep disorders. [ABSTRACT FROM AUTHOR]

The role of melatonin in humans still remains unclear. Uncertainties persist about its effects on neurophysiology regarding its levels in human cerebrospinal fluid (CSF), as the bulk of knowledge on this subject mainly derives from studies conducted on animals. In this study, CSF was micro-sampled with a simple, new method from each cerebral ventricle of patients undergoing neuroendoscopy for hydrocephalus. Our purpose was to measure CSF melatonin levels and determine possible differences in its concentration among various significant areas in the cerebral ventricles (e.g. pineal recess, pituitary recess, lateral ventricle, fourth ventricle) and lumbar cistern. From 2002 to 2004, 10 hydrocephalic patients were operated on using a neuroendoscopic technique. The CSF specimens were investigated for melatonin concentrations (free plus protein-bound) after deproteinization; the measurement technique was high-performance liquid chromatography. The preliminary data obtained with this endoscopic micro-sampling technique (applied to humans for the first time) suggest that melatonin is more concentrated within the ventricles and its highest concentration is found in the third ventricle (IIIv), although the difference detected between the CSF of the IIIv and that of the pineal recess was not significant. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT1 and MT2, but also through an MLT type-3 receptor (MT3). However, the role of MLT receptor subtypes in thermoregulation is still unknown. We have thus investigated the effects of selective and non-selective MLT receptor agonists/antagonists on body temperature (Tb) in rats across the 12/12-h light–dark cycle. Rectal temperature was measured every 15 min from 4:00 a.m. to 9:30 a.m. and from 4:00 p.m. to 9:30 p.m., following subcutaneous injection of each compound at either 5:00 a.m. or 5:00 p.m. MLT (40 mg/kg) had no effect when injected at 5 a.m., whereas it decreased Tb during the light phase only when injected at 5:00 p.m. This effect was blocked by the selective MT2 receptor antagonist 4P-PDOT and the non-selective MT1/MT2 receptor antagonist, luzindole, but not by the α1/MT3 receptors antagonist prazosin. However, unlike MLT, neither the selective MT1 receptor partial agonist UCM871 (14 mg/kg) nor the selective MT2 partial agonist UCM924 (40 mg/kg) altered Tb during the light phase. In contrast, UCM871 injected at 5:00 p.m. increased Tb at the beginning of the dark phase, whereas UCM924 injected at 5:00 a.m. decreased Tb at the end of the dark phase. These effects were blocked by luzindole and 4P-PDOT, respectively. The MT3 receptor agonist GR135531 (10 mg/kg) did not affect Tb. These data suggest that the simultaneous activation of both MT1 and MT2 receptors is necessary to regulate Tb during the light phase, whereas in a complex but yet unknown manner, they regulate Tb differently during the dark phase. Overall, MT1 and MT2 receptors display complementary but also distinct roles in modulating circadian fluctuations of Tb. [ABSTRACT FROM AUTHOR]

The pharmacological potential of targeting selectively melatonin MT1 or MT2 receptors has not yet been exploited in medicine. Research using selective MT1/MT2 receptor ligands and MT1/MT2 receptor knockout mice has indicated that the activation of MT2 receptors selectively increases non‐rapid eye movement (NREM) sleep whereas MT1 receptors seem mostly implicated in the regulation of REM sleep. Moreover, MT1 knockout mice show an increase in NREM sleep, while MT2 knockout a decrease, suggesting an opposite role of these two receptors. A recent paper in mice by Sharma et al (J Pineal Res, 2018, e12498) found that MT1 but not MT2 receptors are expressed on orexin neurons in the perifornical lateral hypothalamus (PFH). Moreover, after injecting melatonin or luzindole into the mouse PFH, the authors suggest that melatonin promotes NREM sleep because activates PFH MT1 receptors, which in turn inhibit orexin neurons that are important in promoting arousal and maintaining wakefulness. In this commentary, we have critically commented on some of these findings on the bases of previous literature. In addition, we highlighted the fact that no conclusions could be drawn on the melatonin receptor subtype mediating the effects of melatonin on sleep because the authors used the non‐selective MT1/MT2 receptors antagonist luzindole. More solid research should further characterize the pharmacological function of these two melatonin receptors in sleep. [ABSTRACT FROM AUTHOR]

Background: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. Methods: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. Results: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. Conclusions: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition. [ABSTRACT FROM AUTHOR]

Abstract: Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT1 and MT2. However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT2-selective partial agonist, UCM765 to evaluate the involvement of MT2 receptors in anxiety. Adult male rats were acutely injected with UCM765 (5–10–20mg/kg), MLT (20mg/kg) or diazepam (DZ, 1mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10mg/kg) or MLT (20mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT1/MT2 antagonist luzindole (10mg/kg) or the MT2 antagonist 4P-PDOT (10mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT2-receptors may be considered a novel target for the development of anxiolytic drugs. [Copyright &y& Elsevier]

Among the troika of clinicopathologic features of asthma, airway remodelling has gained sufficient attention for its contribution to progressive airway narrowing. Much effort has been directed at the management of airway smooth muscle cells (ASMCs), but few attempts have proven to prevent the progression of remodelling. Recently, accumulating data have shown the anti-inflammatory/anti-proliferative potency of melatonin (a crucial neurohormone involved in many physiological and pathological processes) in diverse cells. However, no evidence has confirmed its effect on ASMCs. The present study investigates the benefits of melatonin in asthma, with an emphasis on airway remodelling. The results indicated that melatonin significantly attenuated airway hyperresponsiveness (AHR), inflammation and remodelling in a house dust mite (HDM) model. Melatonin markedly alleviated goblet cell hyperplasia/metaplasia, collagen deposition and airway smooth muscle hyperplasia/hypertrophy, implying the achievement of remodelling remission. The data obtained in vitro further revealed that melatonin notably inhibited ASMCs proliferation, VEGF synthesis and cell migration induced by PDGF, which might depend on STAT3 signalling. Moreover, melatonin remarkably relieved ASMCs contraction and reversed ASMCs phenotype switching induced by TGF-β, probably via the Akt/GSK-3β pathway. Altogether, our findings illustrated for the first time that melatonin improves asthmatic airway remodelling by balancing the phenotypic proportions of ASMCs, thus highlighting a novel purpose for melatonin as a potent option for the management of asthma. [ABSTRACT FROM AUTHOR]

Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl} acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action. In rat L5-L6 spinal nerve ligation and spared nerve injury models, UCM924 (20-40 mg/kg, subcutaneously) produced a prolonged antinociceptive effect that is : (1) dose-dependent and blocked by the selective MT2 receptor antagonist 4-phenyl-2-propionamidotetralin, (2) superior to a high dose of MLT (150 mg/kg) and comparable with gabapentin (100 mg/kg), but (3) without noticeable motor coordination impairments in the rotarod test. Using double staining immunohistochemistry, we found that MT2 receptors are expressed by glutamatergic neurons in the rostral ventrolateral periaqueductal gray. Using in vivo electrophysiology combined with tail flick, we observed that microinjection of UCM924 into the ventrolateral periaqueductal gray decreased tail flick responses, depressed the firing activity of ON cells, and activated the firing of OFF cells; all effects were MT2 receptor-dependent. Altogether, these data demonstrate that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending antinociceptive pathways, and MT2 receptors may represent a novel target in the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]