Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways
Articolo
Data di Pubblicazione:
2015
Citazione:
Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways / M. Lopez Canul, E. Palazzo, S. Dominguez Lopez, L. Luongo, B. Lacoste, S. Comai, D. Angeloni, F. Fraschini, S. Boccella, G. Spadoni, A. Bedini, G. Tarzia, S. Maione, V. Granados Soto, G. Gobbi. - In: PAIN. - ISSN 0304-3959. - 156:2(2015 Feb), pp. 305-317. [10.1097/01.j.pain.0000460311.71572.5f]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
MT2 receptors; UCM924; Neuropathic pain; Periaqueductal gray; ON/OFF cells; Rostral ventromedial medulla; Melatonin
Elenco autori:
M. Lopez Canul, E. Palazzo, S. Dominguez Lopez, L. Luongo, B. Lacoste, S. Comai, D. Angeloni, F. Fraschini, S. Boccella, G. Spadoni, A. Bedini, G. Tarzia, S. Maione, V. Granados Soto, G. Gobbi
Link alla scheda completa: