We appreciate the insightful comments by Dr. Ruan and Dr. Luo, especially from their clinical points of view. We thank them for their remark on our findings, i.e. that the agonistic activity at the central delta opioid receptor contributes to oxycodone supraspinal antinociception in mice may explain the discrepancy between poor opioid receptor binding and analgesic efficacy of oxycodone [1]. Dr. Ruan and Dr. Luo wonder whether our results would have been consistent if female MOR-KO mice had been used. Regarding to this point, we are not able to make a statement because we have not done this type of experiments with female MOR-KO mice. As Dr. Ruan and Dr. Luo mentioned, pain sensitivity changes over the course of the menstrual cycle in women [2] and pain threshold changes as a function of estrus cycle in female rats [3], therefore we chose to use male mice to do this study. From a recent review which concluded that estrogen facilitates KOR or MOR mediated antinociceptive effects of i.t. (-)-pentazocine in female rats [4], I think the agonism at delta-opioid receptors will contribute to the antinociceptive effect of oxycodone in female mice, but the degree of antinociceptive effects of oxycodone or sensitivity to oxycodone may differ from that in the male mice due to estrogen’s effect.
