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.