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Based on this, some mechanistic explanations have been proposed for the loss of strong opioid effectiveness in NP conditions, including the release of dynorphin [67], the downregulation of MOR in the spinal cord [76,77] and dorsal root ganglion (DRG) [78,79], the increase in the serotonin level [80], increased methylation of the MOR gene promoter in DRG and/or the stimulation of glutamate receptor [81], the decrease in morphine concentration in the brain [86], etc