Peripheral Administration of an Opioid Peptide Analog Ameliorates Morphine-Produced Hyperalgesia in a Spared Nerve Injury Model

Traditional opioids have proven analgesic effects in clinical applications but are also associated with side effects, especially hyperalgesia. Reducing the occurrence of hyperalgesia is part of effective clinical pain management. In this study, we investigated the difference between MEL-0614, a novel endomorphin analog that can effectively penetrate the blood–brain barrier, and morphine in inducing hyperalgesia. Under mechanical and thermal stimulation conditions, intravenous administration of morphine led to hyperalgesia even at low concentrations, which was not observed with MEL-0614 even at high concentrations. In a spared nerve injury model, significantly less aggravation of allodynia was caused by an intravenous injection of MEL-0614 compared with that caused by morphine, and the allodynia symptoms occurred later. Notably, MEL-0614 significantly relieved the symptoms of morphine-induced allodynia. The activation of N-methyl-d-aspartic acid receptor and expression of inflammatory mediators differed in spinal microglia after intravenous injections of MEL-0614 and morphine. Intravenous injections of morphine induced increases in the number of microglia and overexpression of inflammatory factors, including tumor necrotic factor and interleukin-1β. Conversely, the effects of MEL-0614 administration did not differ from those of saline, and there was no inflammatory mediator overexpression. Especially in the spared nerve injury model, the cross-administration of morphine and MEL-0614 could reduce the expression of Toll-like receptor 4 and other related genes to different degrees compared with the use of morphine alone. Concurrently, the results could also explain the alleviating effect of MEL-0614 on morphine-induced pain sensitivity in behavioral experiments. Our findings may provide important information regarding the clinical treatment of neuropathic pain in the future.