Supraspinal melatonin MT 2 receptor agonism alleviates pain via a neural circuit that recruits mu opioid receptors.

Melatonin, through its G protein-coupled MT receptor, is implicated in analgesia, but the relationship between MT receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured, SNI), the selective melatonin MT agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the non-selective opioid antagonist naloxone and the selective MOR antagonist CTOP blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pro-nociceptive ON-cells, and the enhancement of the firing of the anti-nociceptive OFF-cells, induced by the microinjection of the MT agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT receptors are expressed in both excitatory (CaMKIIα ) and inhibitory (GAD65 ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons co-expressed MOR and MT receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT receptor agonism requires MORs to exert its antiallodynic effects, mostly through an inter-neuronal circuit involving MOR and MT receptors. This article is protected by copyright. All rights reserved.