title: Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways.
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.
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, QC, Canada Institute of Neuroethology, University Veracruzana, Xalapa, México Department of Experimental Medicine, Second University of Naples, Naples, Italy Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy Institute of Medicinal Chemistry, University Carlo Bo, Urbino, Italy Neurobiology of Pain Laboratory, Department of Pharmacobiology, Cinvestav-Sede Sur, México, D. F., Mexico.
authors.forename: Martha
authors.initials: M
authors.lastname: Lopez-Canul
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Sergio
authors.initials: S
authors.lastname: Dominguez-Lopez
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Baptiste
authors.initials: B
authors.lastname: Lacoste
authors.forename: Stefano
authors.initials: S
authors.lastname: Comai
authors.forename: Debora
authors.initials: D
authors.lastname: Angeloni
authors.forename: Franco
authors.initials: F
authors.lastname: Fraschini
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vinicio
authors.initials: V
authors.lastname: Granados-Soto
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
mesh_terms: D000081:Acetamides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000814:Aniline Compounds / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000814:Aniline Compounds; D008024:Ligands; C545681:N-(2-((3-bromophenyl)-(4-fluorophenyl)amino)ethyl)acetamide; D044123:Receptor, Melatonin, MT2