Activation of spinal melatonin MT2 receptors reduces neuropathic pain in mice in a sex-dependent manner.

Previous studies have reported the effects of melatonin mainly in male rodents. However, the effect of sex on the effect of melatonin remains unknown. The purpose of this study was to evaluate the role of sex in the antiallodynic effect of melatonin under neuropathic pain conditions. Intrathecal melatonin reduced both evoked and spontaneous pain in female and male neuropathic mice, with a significantly greater effect in female mice. Selective blockade of spinal melatonin MT2, but not MT1, receptors abated the antiallodynic effect of melatonin in both sexes. In contrast, blockade of spinal opioid receptors abated the antiallodynic effect of melatonin in male mice and partially in female mice. Notably, ovariectomy eliminated the antiallodynic effect of melatonin in female mice. Additionally, 17β-estradiol or estrogen receptor-α agonist PPT treatment, but not estrogen receptor-β agonist DPN, restored the antiallodynic effect of melatonin in ovariectomized female mice. Furthermore, blocker of estrogen receptor-α/β ICI-182,780 or estrogen receptor-α MPP prevented the effect of 17β-estradiol on melatonin-induced antiallodynia in ovariectomized female mice. Our results indicate a sex-dependent mechanism in melatonin-induced antiallodynic effect in mice. While the activation of melatonin MT2 receptors mediates the effect of melatonin in both female and male mice, activation of spinal opioid receptors plays a more relevant role in male mice. Additionally, the effects of melatonin in females depend on the activation of spinal estrogen receptor-α.