38 results on '"Comai, Stefano"'
Search Results
2. Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT1 Receptors Located in the Locus Ceruleus Norepinephrine Neurons.
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López-Canul, Martha, Qianzi He, Sasson, Tania, Ettaoussi, Mohamed, De Gregorio, Danilo, Ochoa-Sanchez, Rafael, Catoire, Helene, Posa, Luca, Rouleau, Guy, Beaulieu, Jean Martin, Comai, Stefano, and Gobbi, Gabriella
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RAPID eye movement sleep ,NON-REM sleep ,NORADRENALINE ,NEURONS ,RATS ,MELATONIN - Abstract
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 MT
1 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]- Published
- 2024
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3. Investigating the relationship between melatonin levels, melatonin system, microbiota composition and bipolar disorder psychopathology across the different phases of the disease
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Manchia, Mirko, Squassina, Alessio, Pisanu, Claudia, Congiu, Donatella, Garzilli, Mario, Guiso, Beatrice, Suprani, Federico, Paribello, Pasquale, Pulcinelli, Vittoria, Iaselli, Maria Novella, Pinna, Federica, Valtorta, Flavia, Carpiniello, Bernardo, and Comai, Stefano
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- 2019
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4. Age-related effects of exogenous melatonin on anxiety-like behavior in C57/B6J mice
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Nasini, Sofia, Tidei, Sara, Shkodra, Atea, De Gregorio, Danilo, Cambiaghi, Marco, and Comai, Stefano
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sociability ,mice ,melatonin ,anxiety ,adolescents ,adults ,local field potentials ,hippocampus ,medial prefrontal cortex ,aging - Published
- 2023
5. Acute and Chronic Pain Preclinical Models to Study the Analgesic Properties of Melatonergic Compounds
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De Gregorio, Danilo and Comai, Stefano
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Analgesia ,Hot plate test ,Melatonin ,Pain ,Spared nerve injury - Published
- 2022
6. Photothrombotic Mouse Models for the Study of Melatonin as a Therapeutic Tool After Ischemic Stroke
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Cambiaghi, Marco, Cherchi, Laura, and Comai, Stefano
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Brain ischemia ,Photothrombotic model ,Neuroprotection ,Melatonin - Published
- 2022
7. Melatonin and aggressive behavior: A systematic review of the literature on preclinical and clinical evidence.
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Paribello, Pasquale, Manchia, Mirko, Bosia, Marta, Pinna, Federica, Carpiniello, Bernardo, and Comai, Stefano
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AGGRESSION (Psychology) ,MELATONIN ,VIOLENCE ,IRRITABILITY (Psychology) ,CIRCADIAN rhythms ,PREMENSTRUAL syndrome - Abstract
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]
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- 2022
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8. Melatonin recovers sleep phase delayed by MK‐801 through the melatonin MT2 receptor‐ Ca2+‐CaMKII‐CREB pathway in the ventrolateral preoptic nucleus.
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Wang, Qian, Zhu, Dexiao, Ping, Shuo, Li, Chuangang, Pang, Kunkun, Zhu, Shaowei, Zhang, Jing, Comai, Stefano, and Sun, Jinhao
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MELATONIN ,SUPRACHIASMATIC nucleus ,METHYL aspartate receptors ,ADENO-associated virus ,ANIMAL models in research - Abstract
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]
- Published
- 2020
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9. Dysfunction of serotonergic activity and emotional responses across the light‐dark cycle in mice lacking melatonin MT2 receptors.
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Comai, Stefano, De Gregorio, Danilo, Posa, Luca, Ochoa‐Sanchez, Rafael, Bedini, Annalida, and Gobbi, Gabriella
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RAPHE nuclei , *MICE , *EYE movements , *NEURAL transmission - Abstract
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]
- Published
- 2020
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10. Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives.
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Comai, Stefano, Lopez-Canul, Martha, De Gregorio, Danilo, Posner, Ada, Ettaoussi, Mohamed, Guarnieri, Fabrizia Claudia, and Gobbi, Gabriella
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G protein coupled receptors , *HUNTINGTON disease , *SUPRACHIASMATIC nucleus , *NEUROLOGICAL disorders , *PSYCHIATRIC drugs , *SLOW wave sleep - Abstract
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]
- Published
- 2019
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11. Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep.
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Gobbi, Gabriella and Comai, Stefano
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SLEEP ,MELATONIN ,RAPID eye movement sleep ,NON-REM sleep ,SLEEP disorders - Abstract
The pathophysiological function of the G-protein coupled melatonin MT
1 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]- Published
- 2019
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12. Antinociceptive properties of selective MT2 melatonin receptor partial agonists.
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López-Canul, Martha, Comai, Stefano, Domínguez-López, Sergio, Granados-Soto, Vinicio, and Gobbi, Gabriella
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ANALGESICS , *METALLOTHIONEIN , *MELATONIN , *NEUROHORMONES , *ANIMAL models in research - Abstract
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]
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- 2015
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13. Melatonin, selective and non-selective MT1/MT2 receptors agonists: Differential effects on the 24-h vigilance states.
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Ochoa-Sanchez, Rafael, Comai, Stefano, Spadoni, Gilberto, Bedini, Annalida, Tarzia, Giorgio, and Gobbi, Gabriella
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MELATONIN , *HORMONE receptors , *VIGILANCE (Psychology) , *SLEEP-wake cycle , *WAKEFULNESS , *NEUROPHARMACOLOGY , *THERAPEUTICS - Abstract
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]
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- 2014
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14. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology.
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Comai, Stefano and Gobbi, Gabriella
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ANXIETY , *CELL receptors , *MELATONIN , *MENTAL illness , *SLEEP , *DRUG development - Abstract
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]
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- 2014
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15. Sleep–wake characterization of double MT1/MT2 receptor knockout mice and comparison with MT1 and MT2 receptor knockout mice
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Comai, Stefano, Ochoa-Sanchez, Rafael, and Gobbi, Gabriella
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NEUROHORMONES , *SLEEP-wake cycle , *MELATONIN , *LABORATORY mice , *G protein coupled receptors , *CIRCADIAN rhythms - Abstract
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]
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- 2013
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16. Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT2 Melatonin Receptor Ligand.
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Ochoa-Sanchez, Rafael, Comai, Stefano, Lacoste, Baptiste, Bambico, Francis Rodriguez, Dominguez-Lopez, Sergio, Spadoni, Gilberto, Rivara, Silvia, Bedini, Annalida, Angeloni, Debora, Fraschini, Franco, Mor, Marco, Tarzia, Giorgio, Descarries, Laurent, and Gobbi, Gabriella
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MELATONIN , *RAPID eye movement sleep , *RETICULAR formation , *THALAMUS , *NEURONS , *HORMONE receptors , *LIGANDS (Biochemistry) - Abstract
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]
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- 2011
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17. Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique.
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Longatti, Pierluigi, Perin, Alessandro, Rizzo, Vittoria, Comai, Stefano, Giusti, Pietro, and Luigi Costa, Carlo Virgilio
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MELATONIN ,NEUROPHYSIOLOGY ,CEREBROSPINAL fluid ,HYDROCEPHALUS ,LIQUID chromatography ,BODY fluids - Abstract
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]
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- 2007
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18. Melatonin MT1 and MT2 Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle.
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López-Canul, Martha, Min, Seung Hyun, Posa, Luca, De Gregorio, Danilo, Bedini, Annalida, Spadoni, Gilberto, Gobbi, Gabriella, and Comai, Stefano
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MELATONIN ,BODY temperature ,CIRCADIAN rhythms ,G protein coupled receptors ,PRAZOSIN - Abstract
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 MT
1 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]- Published
- 2019
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19. Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep.
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Gobbi, Gabriella and Comai, Stefano
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KNOCKOUT mice , *RAPID eye movement sleep , *EYE movements - Abstract
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]
- Published
- 2019
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20. Melancholic-Like Behaviors and Circadian Neurobiological Abnormalities in Melatonin MT1 Receptor Knockout Mice.
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Comai, Stefano, Ochoa-Sanchez, Rafael, Dominguez-Lopez, Sergio, Bambico, Francis Rodriguez, and Gobbi, Gabriella
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MENTAL depression ,NERVOUS system abnormalities ,MELATONIN ,LABORATORY mice ,PHENOTYPES - Abstract
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]
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- 2015
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21. Anxiolytic effects of the melatonin MT2 receptor partial agonist UCM765: Comparison with melatonin and diazepam
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Ochoa-Sanchez, Rafael, Rainer, Quentin, Comai, Stefano, Spadoni, Gilberto, Bedini, Annalida, Rivara, Silvia, Fraschini, Franco, Mor, Marco, Tarzia, Giorgio, and Gobbi, Gabriella
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TRANQUILIZING drugs , *MELATONIN , *DIAZEPAM , *NEUROHORMONES , *ANXIETY , *G protein coupled receptors , *PHARMACODYNAMICS - Abstract
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]
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- 2012
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22. Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma.
- Author
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Yu, Qijun, Yu, Xiaowei, Zhong, Xiuhua, Ma, Yuan, Wu, Yan, Bian, Tao, Huang, Mao, and Zeng, Xiaoning
- Subjects
MELATONIN ,SMOOTH muscle ,MUSCLE cells ,HOUSE dust mites ,ASTHMA ,CELL migration ,ANKLE - Abstract
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]
- Published
- 2020
- Full Text
- View/download PDF
23. Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways.
- Author
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Lopez-Canul, Martha, Palazzo, Enza, Dominguez-Lopez, Sergio, Luongo, Livio, Lacost, Baptiste, Comai, Stefano, Angeloni, Debora, Fraschini, Franco, Boccella, Serena, Spadoni, Gilberto, Bedini, Annalida, Tarzia, Giorgio, Maione, Sabatino, Granados-Soto, Vinicio, and Gobbi, Gabriella
- Subjects
- *
MELATONIN , *HORMONE receptors , *LIGANDS (Biochemistry) , *ANALGESICS , *NEURALGIA , *BRAIN stem , *PATIENTS , *THERAPEUTICS - Abstract
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]
- Published
- 2015
- Full Text
- View/download PDF
24. Melatonin recovers sleep phase delayed by MK‐801 through the melatonin MT 2 receptor‐ Ca 2+ ‐CaMKII‐CREB pathway in the ventrolateral preoptic nucleus
- Author
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Jinhao Sun, Chuangang Li, Stefano Comai, Kunkun Pang, Dexiao Zhu, Shaowei Zhu, Shuo Ping, Jing Zhang, Qian Wang, Wang, Qian, Zhu, Dexiao, Ping, Shuo, Li, Chuangang, Pang, Kunkun, Zhu, Shaowei, Zhang, Jing, Comai, Stefano, and Sun, Jinhao
- Subjects
0301 basic medicine ,medicine.medical_specialty ,MT2 receptors ,medicine.drug_class ,receptors ,melatonin ,CREB ,NMDA receptors ,Non-rapid eye movement sleep ,Melatonin ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Ca2+/calmodulin-dependent protein kinase ,medicine ,sleep ,calcium ,homeostatic mechanism ,MT ,2 ,Receptor ,biology ,Chemistry ,Suprachiasmatic nucleus ,Receptor antagonist ,030104 developmental biology ,biology.protein ,NMDA receptor ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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 non-rapid 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.
- Published
- 2020
25. Melatonin, selective and non-selective MT1/MT2 receptors agonists: Differential effects on the 24-h vigilance states
- Author
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Gilberto Spadoni, Gabriella Gobbi, Annalida Bedini, Giorgio Tarzia, Stefano Comai, Rafael Ochoa-Sanchez, Ochoa Sanchez, Rafael, Comai, Stefano, Spadoni, Gilberto, Bedini, Annalida, Tarzia, Giorgio, and Gobbi, Gabriella
- Subjects
Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,receptor ,media_common.quotation_subject ,Sleep, REM ,UCM793 ,Non-rapid eye movement sleep ,Partial agonist ,Rats, Sprague-Dawley ,Melatonin ,Sleep-wake cycle ,UCM924 ,Internal medicine ,Acetamides ,medicine ,Animals ,Circadian rhythm ,Wakefulness ,media_common ,First episode ,Aniline Compounds ,Receptor, Melatonin, MT2 ,Receptor, Melatonin, MT1 ,General Neuroscience ,MT ,1 ,2 ,Electroencephalography ,Drug Partial Agonism ,Endocrinology ,Anesthesia ,Sleep Stages ,Psychology ,psychological phenomena and processes ,medicine.drug ,Vigilance (psychology) - Abstract
Melatonin (MLT) is a neurohormone implicated in several physiological processes such as sleep. Contrasting results have been produced on whether or not it may act as a hypnotic agent, and the neurobiological mechanism through which it controls the vigilance states has not yet been elucidated. In this study we investigated the effect of MLT (40 mg/kg), a non-selective MT1/MT2 receptor agonist (UCM793, 40 mg/kg), and a selective MT2 partial agonist (UCM924, 40 mg/kg) on the 24-h vigilance states. EEG and EMG sleep-wake patterns were registered across the 24-h light-dark cycle in adult Sprague-Dawley male rats. MLT decreased (-37%) the latency to the first episode of non rapid eye movement sleep (NREMS), enhanced the power of NREMS delta band (+33%), but did not alter the duration of any of the three vigilance states. Differently, UCM793 increased the number of episodes (+52%) and decreased the length of the episodes (-38%) of wakefulness but did not alter the 24-h duration of wakefulness, NREMS and REMS. UCM924 instead reduced the latency (-56%) and increased (+31%) the duration of NREMS. Moreover, it raised the number of REMS episodes (+57%) but did not affect REMS duration. Taken together, these findings show that MLT and non-selective MT1/MT2 receptor agonists do not increase the quantity of sleep but differently influence the three vigilance states. In addition, they support the evidence that selective MT2 receptor agonists increase NREMS duration compared to MLT and non-selective MT1/MT2 agonists.
- Published
- 2014
26. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology
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Gabriella Gobbi, Stefano Comai, Comai, Stefano, and Gobbi, Gabriella
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business.industry ,medicine.disease ,Melatonin ,Psychiatry and Mental health ,Pineal gland ,medicine.anatomical_structure ,Mood disorders ,Medicine ,Anxiety ,Pharmacology (medical) ,Psychopharmacology ,Circadian rhythm ,medicine.symptom ,Receptor ,business ,Neuroscience ,Biological Psychiatry ,G protein-coupled receptor ,medicine.drug - Abstract
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.
- Published
- 2014
27. Targeting Melatonin MT2 Receptors: A Novel Pharmacological Avenue for Inflammatory and Neuropathic Pain
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Stefano Comai, Danilo De Gregorio, Luca Posa, Gabriella Gobbi, Posa, Luca, De Gregorio, Danilo, Gobbi, Gabriella, and Comai, Stefano
- Subjects
0301 basic medicine ,Analgesic ,receptors ,Chronic pain ,ON/OFF cell ,Pharmacology ,Biochemistry ,Partial agonist ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Mt ,Drug Discovery ,Acetamides ,medicine ,receptors partial agonists ,Animals ,Humans ,MT2 receptor ,Receptor ,Melatonin ,Inflammation ,Analgesics ,Aniline Compounds ,business.industry ,Receptor, Melatonin, MT2 ,Organic Chemistry ,Clinical Studies as Topic ,ON/OFF cells ,Brain ,medicine.disease ,acute/inflammatory pain ,030104 developmental biology ,Mechanism of action ,Spinal Cord ,Acute/inflammatory pain ,MT2 receptors partial agonist ,Neuropathic pain ,Molecular Medicine ,Neuralgia ,Rostral ventromedial medulla ,medicine.symptom ,chronic pain ,business ,030217 neurology & neurosurgery ,2 - Abstract
Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G-protein coupled receptors, MT1 and MT2. In this review, we present the analgesic properties of MLT in preclinical and clinical studies, giving particular emphasis to the effects mediated by MT2 receptors and to recent investigations demonstrating the analgesic effects of MT2 receptor partial agonists in chronic and acute/inflammatory pain conditions. MT2 receptors are localized in specific brain areas, including the reticular and the ventromedial nuclei of the thalamus (part of the ascending nociceptive pathway) and the ventrolateral periaqueductal grey matter (vlPAG) (part of the descending antinociceptive pathway). MLT displays analgesic properties in several animal paradigms of chronic, acute, inflammatory and neuropathic pain; importantly, these effects are mediated by MT2 receptors since they are blocked by selective MT2 antagonists. In different pain paradigms, UCM924 and UCM765, two selective MT2 receptor partial agonists, produce analgesic effects with higher potency than MLT, thus confirming the involvement of MT2 receptors in pain. Notably, these compounds do not induce sedation and motor impairments. Although their analgesic mechanism of action is not yet completely elucidated, they act on antinociceptive descending pathways by stimulating MT2 receptors on glutamatergic neurons of the vlPAG, which in turn activate OFF cells and inhibit ON cells of the rostral ventromedial medulla (RVM). Collectively, there is strong preclinical evidence suggesting the pharmacological potential of MT2 receptor partial agonists, which also have a favorable toxicological profile. These compounds may be further developed as novel analgesic drugs.
- Published
- 2016
28. Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep
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Gabriella Gobbi, Stefano Comai, Gobbi, Gabriella, and Comai, Stefano
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Lateral hypothalamus ,melatonin ,MT1 receptor ,Melatonin receptor ,Non-rapid eye movement sleep ,Melatonin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Animals ,Medicine ,MT2 receptor ,sleep ,Receptor ,Neurons ,Receptor, Melatonin, MT2 ,business.industry ,Receptor, Melatonin, MT1 ,orexin ,Orexin ,030104 developmental biology ,Knockout mouse ,Sleep ,business ,Luzindole ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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.
- Published
- 2019
29. Antinociceptive properties of selective MT2 melatonin receptor partial agonists
- Author
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Stefano Comai, Sergio Dominguez-Lopez, Gabriella Gobbi, Martha Lopez-Canul, Vinicio Granados-Soto, Lopez Canul, Martha, Comai, Stefano, Dominguez Lopez, Sergio, Granados Soto, Vinicio, and Gobbi, Gabriella
- Subjects
Male ,Nociception ,receptor partial agonists ,Time Factors ,Tetrahydronaphthalenes ,Analgesic ,Acute pain ,Antinociception ,Formalin test ,Hot-plate test ,Melatonin ,MT ,2 ,Pharmacology ,Partial agonist ,Melatonin receptor ,Nociceptive Pain ,Formaldehyde ,Acetamides ,medicine ,Animals ,Hot plate test ,Rats, Wistar ,Acetaminophen ,Analgesics ,Aniline Compounds ,Behavior, Animal ,Dose-Response Relationship, Drug ,Chemistry ,Receptor, Melatonin, MT2 ,Antagonist ,Brain ,Drug Partial Agonism ,Disease Models, Animal ,Neuropathic pain ,Ketorolac ,medicine.drug ,Protein Binding ,Signal Transduction - Abstract
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 MT2 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 MT2 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 20mg/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 MT2 partial agonists were blocked by the pre-treatment with the MT2 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 MT2 melatonin receptor may be a novel target for analgesic drug development.
- Published
- 2015
30. Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways
- Author
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Serena Boccella, Giorgio Tarzia, Franco Fraschini, Stefano Comai, Sabatino Maione, Gilberto Spadoni, Annalida Bedini, Enza Palazzo, Debora Angeloni, Sergio Dominguez-Lopez, Livio Luongo, Martha Lopez-Canul, Vinicio Granados-Soto, Gabriella Gobbi, Baptiste Lacoste, Lopez Canul, M, Palazzo, Enza, Dominguez Lopez, S, Luongo, Livio, Lacoste, B, Comai, S, Angeloni, D, Fraschini, F, Boccella, S, Spadoni, G, Bedini, A, Tarzia, G, Maione, Sabatino, Granados Soto, V, Gobbi, G., Lopez Canul, Martha, Dominguez Lopez, Sergio, Lacoste, Baptiste, Comai, Stefano, Angeloni, Debora, Fraschini, Franco, Boccella, Serena, Spadoni, Gilberto, Bedini, Annalida, Tarzia, Giorgio, Granados Soto, Vinicio, and Gobbi, Gabriella
- Subjects
Male ,Gabapentin ,medicine.drug_class ,MT2 receptors ,Analgesic ,Pyramidal Tracts ,Wistar ,Periaqueductal gray ,Pharmacology ,Ligands ,Neuropathic pain ,Partial agonist ,UCM924 ,Acetamides ,medicine ,Animals ,Rats, Wistar ,Receptor ,Pain Measurement ,Melatonin ,Aniline Compounds ,Receptor, Melatonin, MT2 ,Chemistry ,MT2 ,ON/OFF cells ,Nerve injury ,Receptor antagonist ,Rats ,Anesthesiology and Pain Medicine ,Nociception ,Neurology ,MT2 receptors,UCM924 ,Periaqueductal gray,ON/OFF cells,Rostral ventromedial medulla,Melatonin ,Neuralgia ,Neurology (clinical) ,Brain Stem ,Rostral ventromedial medulla ,medicine.symptom ,Neuroscience ,medicine.drug - Abstract
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.
- Published
- 2015
31. An investigation on the possible role of melatonin in melanogenesis
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Antonella Bertazzo, Andrea Rizzi, Pietro Traldi, Stefano Comai, Graziella Allegri, Carlo Virgilio Luigi Costa, Rizzi, A, Comai, Stefano, Bertazzo, A, Costa, Cvl, Allegri, G, and Traldi, P.
- Subjects
Melanins ,Models, Molecular ,chemistry.chemical_classification ,biology ,Ultraviolet Rays ,Hydrogen Peroxide ,Oligomer ,Melanin ,Melatonin ,chemistry.chemical_compound ,Matrix-assisted laser desorption/ionization ,Ultrafiltration (renal) ,Enzyme ,Models, Chemical ,chemistry ,Biochemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,medicine ,Biophysics ,Hydrogen peroxide ,Spectroscopy ,Peroxidase ,medicine.drug - Abstract
The possible role of melatonin in melanogenesis was investigated by performing reactions of melatonin with peroxidase + H2O2 or H2O2 only, in the presence or absence of UV irradiation. Samples of the reaction mixtures were drawn at different times (from 15 to 480 min), the enzyme (when present) was removed by ultrafiltration and the samples so obtained were analyzed by MALDI/MS. The results show that melatonin undergoes oligomerization reaction with peroxidase + H2O2, leading to heptameric species. For high reaction times the MALDI/MS data do not show the formation of larger oligomers, but UV-vis spectroscopy indicates that the oligomerization processes proceed. The failure of MALDI-TOF in the identification of larger oligomers was related to the chemical-physical and morphological behavior of melanins. In the case of UV irradiation, the formation of species originating from the O- and O2 addition to melatonin, which activate new oligomerization channels, has been observed.
- Published
- 2006
32. Sleep-wake characterization of double MT1/MT2 receptor knockout mice and comparison with MT1 and MT2 receptor knockout mice
- Author
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Stefano Comai, Rafael Ochoa-Sanchez, Gabriella Gobbi, Comai, Stefano, Ochoa Sanchez, Rafael, and Gobbi, Gabriella
- Subjects
medicine.medical_specialty ,receptor ,Rapid eye movement sleep ,Biology ,Non-rapid eye movement sleep ,Melatonin receptor ,Melatonin ,Behavioral Neuroscience ,Sleep-wake cycle ,Endocrinology ,stomatognathic system ,MT ,Internal medicine ,Knockout mouse ,medicine ,Wakefulness ,Circadian rhythm ,Knockout mice ,1 ,2 ,Receptor ,psychological phenomena and processes ,medicine.drug - 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.
- Published
- 2013
33. Anxiolytic effects of the melatonin MT2 receptor partial agonist UCM765: Comparison with melatonin and diazepam
- Author
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Annalida Bedini, Silvia Rivara, Giorgio Tarzia, Stefano Comai, Rafael Ochoa-Sanchez, Gilberto Spadoni, Quentin Rainer, Franco Fraschini, Gabriella Gobbi, Marco Mor, Ochoa Sanchez, R, Rainer, Q, Comai, Stefano, Spadoni, G, Bedini, A, Rivara, S, Fraschini, F, Mor, M, Tarzia, G, and Gobbi, G.
- Subjects
Male ,medicine.medical_specialty ,Elevated plus maze ,Tetrahydronaphthalenes ,medicine.drug_class ,Motor Activity ,Anxiety ,Partial agonist ,Anxiolytic ,Open field ,Melatonin ,Rats, Sprague-Dawley ,03 medical and health sciences ,Elevated plus maze test ,Novelty suppressed feeding test ,UCM765 ,0302 clinical medicine ,Internal medicine ,Acetamides ,medicine ,Animals ,Drug Interactions ,Maze Learning ,Biological Psychiatry ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Aniline Compounds ,Diazepam ,Dose-Response Relationship, Drug ,Chemistry ,Receptor, Melatonin, MT2 ,Antagonist ,Feeding Behavior ,Tryptamines ,Rats ,Drug Partial Agonism ,Disease Models, Animal ,Anxiety, Elevated plus maze test, Melatonin, Novelty suppressed feeding test, UCM765 ,Endocrinology ,Anti-Anxiety Agents ,Luzindole ,030217 neurology & neurosurgery ,medicine.drug - 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 MT(1) and MT(2). However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT(2)-selective partial agonist, UCM765 to evaluate the involvement of MT(2) 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 MT(1)/MT(2) antagonist luzindole (10mg/kg) or the MT(2) antagonist 4P-PDOT (10mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT(2)-receptors may be considered a novel target for the development of anxiolytic drugs.
- Published
- 2012
34. Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT(2) Melatonin Receptor Ligand
- Author
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Silvia Rivara, Sergio Dominguez-Lopez, Francis Rodriguez Bambico, Baptiste Lacoste, Marco Mor, Franco Fraschini, Giorgio Tarzia, Gilberto Spadoni, Gabriella Gobbi, Laurent Descarries, Debora Angeloni, Rafael Ochoa-Sanchez, Stefano Comai, Annalida Bedini, Ochoa Sanchez, R, Comai, Stefano, Lacoste, B, Bambico, Fr, Dominguez Lopez, S, Spadoni, G, Rivara, S, Bedini, A, Angeloni, D, Fraschini, F, Mor, M, Tarzia, G, Descarries, L, and Gobbi, G.
- Subjects
Male ,medicine.medical_specialty ,Biology ,Non-rapid eye movement sleep ,Partial agonist ,Melatonin ,Rats, Sprague-Dawley ,Mice ,Thalamus ,Internal medicine ,Acetamides ,medicine ,Animals ,Receptor ,Mice, Knockout ,Neurons ,Aniline Compounds ,Receptor, Melatonin, MT2 ,General Neuroscience ,Antagonist ,Articles ,Blockade ,Rats ,Endocrinology ,Reticular connective tissue ,Systemic administration ,Female ,Sleep ,medicine.drug - Abstract
Melatonin activates two brain G-protein coupled receptors, MT1and MT2, whose differential roles in the sleep–wake cycle remain to be defined. The novel MT2receptor 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 of NREMS by UCM765 is nullified by the pharmacological blockade or genetic deletion of MT2receptors. MT2, but not MT1, knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT2receptors 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 MT2antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT2receptors may represent a novel target for the treatment of sleep disorders.
- Published
- 2011
35. A study of tryptophan metabolism via serotonin in ventricular cerebrospinal fluid in HIV-1 infection using a neuroendoscopic technique
- Author
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Carlo Virgilio Luigi Costa, Graziella Allegri, Alessandro Perin, Antonella Bertazzo, Pierluigi Longatti, Stefano Comai, Vittoria Rizzo, Longatti, P, Perin, A, Comai, Stefano, Bertazzo, A., Rizzo, V, Costa, Cvl, and Allegri, G.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Serotonin ,HIV Infections ,Biology ,Cerebral Ventricles ,Ventriculostomy ,Melatonin ,5-Hydroxytryptophan ,Cerebrospinal fluid ,Virology ,Internal medicine ,medicine ,Humans ,Aged ,Third ventricle ,Tryptophan ,Endoscopy ,Human brain ,Hydroxyindoleacetic Acid ,medicine.disease ,Hydrocephalus ,Infectious Diseases ,Endocrinology ,medicine.anatomical_structure ,HIV-1 ,Choroid plexus ,medicine.drug - Abstract
In this paper we report the study of tryptophan metabolism via serotonin in ventricular CSF in HIV-1 infection in order to investigate the origin of tryptophan metabolites in the human brain. The patients (n=4) were affected with non-communicating hydrocephalus. One of these also was suffering from HIV-1 infection. The CSF was withdrawn from different sites of the cerebral cavity with a neuroendoscopic procedure which allows an accurate exploration of all the cerebral ventricles. The measurement of tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin was carried out by HPLC with fluorometric detection. In HIV-1 infection the highest concentration of tryptophan is present in the CSF of the choroid plexus; however, the levels are markedly lower than those in hydrocephalic individuals (control group). 5-Hydroxytryptophan CSF content is higher in HIV-1 infection than in hydrocephalic controls in all districts examined. Regarding serotonin, a great difference appears in the choroid plexus and in the pituitary recess between the HIV-1 infected patient and the control group. The values of 5-hydroxyindoleacetic acid are much lower in the CSF of the HIV-1 infected patient than in hydrocephalic controls. Melatonin levels appear to fluctuate largely but, in the HIV-1 infection, a great variability is present among the sites of CSF withdrawal. The third ventricle contains the highest concentration of melatonin and the choroid plexus and the pituitary recess the lowest. All the melatonin concentrations in HIV-1 infection are largely different than in hydrocephalic controls. This is the first report on the measurement of tryptophan metabolites via serotonin in ventricular CSF in HIV-1 infection.
- Published
- 2007
36. Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique
- Author
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Alessandro Perin, Pietro Giusti, Carlo Virgilio Luigi Costa, Stefano Comai, Pierluigi Longatti, Vittoria Rizzo, Longatti, P, Perin, A, Rizzo, V, Comai, Stefano, Giusti, P, and Costa, Cvl
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Fourth ventricle ,Cerebral Ventricles ,Melatonin ,Central nervous system disease ,Endocrinology ,Cerebrospinal fluid ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Third ventricle ,business.industry ,Endoscopy ,Middle Aged ,medicine.disease ,Hydrocephalus ,medicine.anatomical_structure ,Ventricle ,Cerebral ventricle ,Female ,business ,medicine.drug - Abstract
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.
- Published
- 2007
37. Melancholic-Like Behaviors and Circadian Neurobiological Abnormalities in Melatonin MT1 Receptor Knockout Mice
- Author
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Gabriella Gobbi, Stefano Comai, Rafael Ochoa-Sanchez, Francis Rodriguez Bambico, Sergio Dominguez-Lopez, Comai, Stefano, Ochoa Sanchez, Rafael, Dominguez Lopez, Sergio, Bambico Francis, Rodriguez, and Gobbi, Gabriella
- Subjects
Male ,Monoamines ,Serotonin ,medicine.medical_specialty ,receptors ,Melancholic depression ,Antidepressive Agents, Tricyclic ,Chronobiology Disorders ,Serotonergic ,Circadian rhythm ,Corticosterone ,Daily mood variations ,MT ,1 ,Norepinephrine ,Melatonin ,Food Preferences ,Mice ,Internal medicine ,Desipramine ,medicine ,Animals ,Pharmacology (medical) ,Maze Learning ,Swimming ,Mice, Knockout ,Pharmacology ,Depressive Disorder ,MT1 receptors ,Receptor, Melatonin, MT1 ,Feeding Behavior ,medicine.disease ,Disease Models, Animal ,Psychiatry and Mental health ,Endocrinology ,Hindlimb Suspension ,Knockout mouse ,Exploratory Behavior ,Locus coeruleus ,Psychology ,Research Article ,medicine.drug - Abstract
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.
- Published
- 2015
38. Endoscopic selective sampling of human ventricular CSF: a new perspective
- Author
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Graziella Allegri, Stefano Comai, Pierluigi Longatti, Antonella Bertazzo, Vittoria Rizzo, Alessandro Perin, Longatti, P, Perin, A, Rizzo, V, Comai, Stefano, Bertazzo, A, and Allegri, G.
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,Pineal Gland ,Cerebral Ventricles ,Central nervous system disease ,Melatonin ,Lateral ventricles ,Cerebrospinal fluid ,Pituitary Gland, Posterior ,medicine ,Humans ,Aged ,Third ventricle ,business.industry ,Tryptophan ,General Medicine ,Hydroxyindoleacetic Acid ,medicine.disease ,Surgery ,Hydrocephalus ,medicine.anatomical_structure ,Neuroendoscopy ,Ventricle ,Drainage ,Feasibility Studies ,Neurology (clinical) ,business ,medicine.drug - Abstract
Neuroendoscopy has achieved extensive acceptance among neurosurgeons as a minimally invasive technique for the treatment of patients affected by blocked hydrocephalus. During endoscopic procedures minimal CSF amounts from selected anatomic sites of the ventricles can be withdrawn. Steerable endoscopes are used and their flexibility facilitates the aspiration of CSF during the preliminary inspection through the ventricular cavities, without any interference with the surgical actions or additional risks for the patients. In this preliminary study the concentrations of melatonin and other related metabolites in the lateral ventricles, third ventricle, pineal recess and infundibular recess were examined. The data obtained from a patient affected by blocked hydrocephalus confirmed a constant and significant difference of concentration of these substances, for instance, melatonin levels were found to be much higher in the third ventricle (542 pg/mL in its centre) than in the lateral ventricle (172 pg/mL in the right ventricle). Nevertheless, instead of what we would expect, the highest melatonin concentrations were not found in the pineal recess (438 pg/mL). In the future, neuroendoscopy, beside its evident therapeutic efficacy, could open new perspectives in the study of both CSF biochemistry and physiology, allowing a highly selective approach to the various substances which are released and float in it.
- Published
- 2005
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