Effects Of Duloxetine On Chronic Pain And Drug Tolerance

The discomfort and pain caused by chronic postoperative pain have been widely concerned.At present,the clinical treatment of postoperative chronic pain is still challenging.Pain and depression are closely related in brain regions and nervous systems.Antidepressants can be used as analgesics in clinic,among which SNRI（Serotonin and Norepinephrine Reuptake Inhibitor）is one of the main drugs.In this study,a plantar skin/muscle incision-PIS model was used to induce mechanical ectopic pain for up to 27 days,which well mimics chronic postoperative pain caused by clinical surgery.In this study,we evaluated the acute analgesic effects of duloxetine and morphine in PIS model.In the hyperalgesia and tolerance trials,long-term duloxetine treatment（30 nmol,i.t）did not induce hyperalgesia and tolerance,while morphine significantly reduced analgesia after 7 consecutive days of administration.It is important to note that morphine-induced hyperalgesia and tolerance can be greatly prevented and/or inhibited by duloxetine.In addition,the results of long-term administration of duloxetine showed that duloxetine could improve postoperative pain and accelerate the recovery of postoperative pain,while morphine aggravated postoperative pain and prolonged the recovery time both before and after surgery.The mechanism of the two drugs were examined by a series of molecular and cellular experiments,which showed that duloxetine treated PIS mice did not activate microglia and P2X4 R signaling pathways,and the expression of inflammatory mediators was lower than that in the morphine group.The experimental results showed that SNRI could enhance the analgesic effect of morphine,and the combination of morphine was not effective to produce obvious hyperalgesia tolerance compared with morphine alone.These results indicate that the combination of SNRI and opioids is of great significance in clinical application,provides a new therapeutic strategy and provide directions for finding new targets of pain about hyperalgesia and tolerance caused by morphine.