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The Effect of Melatonin on Radicular Pain in a Rat Model of Lumbar Disc Herniation

Central sensitization that exaggerates peripheral pain signals is the critical cause of radicular pain from LDH. We identify that systemic delivery of melatonin may alleviate radicular pain by inhibiting central sensitization via its receptor 2. The finding provides new choice for clinical pain management. Study Design. Controlled, randomized, animal study. Objective. To investigate the effect of melatonin and its receptors on radicular pain and the possible mechanisms. Summary of Background Data. Lumbar disc herniation (LDH) may induce radicular pain, but the mechanism is not clear and therapeutic effect is still poor. Previously we report central sensitization meaning potentiation of spinal nociceptive synaptic transmission is the critical cause of radicular pain. Melatonin (Mel) has been reported to promote hippocampal synaptic transmission and thus improve learning ability. But the effect of Mel on spinal synaptic transmission and radicular pain are not clear. Methods. Rat LDH model was induced by autologous nucleus pulposus (NP) implantation. Melatonin was delivered intraperitoneally four times a day, from day 1 to day 3 after surgery. Melatonin receptor agonist and antagonists were delivered intrathecally for 3 days as well. Mechanical and thermal pain thresholds were assessed by von Frey filaments and hotplate test respectively. Electrophysiological recording was employed for survey C-fiber evoked field potentials. The protein level of N- methyl-D-aspartate submit 2A (NR2A), NR2B, melatonin receptor 1 (MT1), and receptor 2 (MT2) was evaluated by western blotting. Spinal expression of calcitonin gene related peptides (CGRP), isolectin b4 (IB4), and neurofilament-200 (NF200) was displayed by immunofluorescence staining. Results. Melatonin significantly increased mechanical and thermal pain thresholds, lasting at least to day 5 after surgery. Melatonin decreased C-fiber evoked field potentials; decreased spinal NR2B protein level; reduced spinal CGRP, and IB4 expression. MT2 was upregulated after NP implantation and was co-localized with neuron and microglia. MT2 receptor agonist simulated the effect of Mel, and both MT receptor broadspectrum antagonist and MT2 specific antagonist abolished the effect of MT2 receptor agonist. Conclusion. Melatonin alleviates radicular pain from LDH by inhibiting central sensitization via binding with its receptor 2, decreasing spinal CGRP, IB4, and NR2B expression.