Title:Targeting Melatonin MT2 Receptors: A Novel Pharmacological Avenue for Inflammatory and Neuropathic Pain
Volume: 25
Issue: 32
Author(s): Luca Posa, Danilo De Gregorio, Gabriella Gobbi*Stefano Comai*
Affiliation:
- Neurobiological Psychiatry Unit, McGill University, Montreal,Canada
- Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan,Italy
Keywords:
Melatonin, MT2 receptors, MT2 receptors partial agonists, ON/OFF cells, chronic pain,
acute/inflammatory pain.
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.
