| Background: More than 300 million operations are performed annually globally,and less than 50% of sufficient postoperative analgesia is clinically.Postoperative pain has greatly affected people’s quality of life,lengthened hospital stays,increased morbidity and treatment costs,and delayed patient recovery.Opioids are commonly used in perioperative analgesics.While they exert analgesic effects,with series of adverse reactions: tolerance,addiction,opioid-induced hyperalgesia(OIH)and hyperalgesic priming.Fentanyl,as a representative of opioids,has been proved to induce hyperalgesia and hyperalgesic priming in animal experiments.But the specific mechanism is unknown.Dexmedetomidine is a highly selective α2 adrenergic receptor agonist with sedative,analgesic,and anxiolytic effects.It is an ideal anesthetic aid.It is reported that dexmedetomidine inhibits OIH by inhibiting the release of inflammatory mediators on spinal microglia and p38 mitogen-activated protein kinase phosphorylation.However,it has not been reported whether dexmedetomidine can inhibit fentanyl-induced hyperalgesia priming.Therefore,we hypothesized that dexmedetomidine inhibits fentanyl-induced hyperalgesia priming by inhibiting the release of inflammatory mediators from spinal cord tissues and phosphorylation of p38 mitogen-activated protein kinase on microglia.Objective: To investigate the mechanism of fentanyl-induced hyperalgesia priming;to explore the role and mechanism of dexmedetomidine in inhibiting fentanyl-induced hyperalgesia priming.Methods: There are two parts in the experiments.In the first part of the experiment,eighteen male Sprageue-Dawley rats of 200-250 g were selected and randomly divided into 3 groups(n=6): Control group(Control),incision + saline group(I+Saline),incision+fentanyl group(I+F).The model of fentanyl-induced hyperalgesia priming was established by plantar incision.Fentanyl was injected subcutaneously 4 times at 60 μg/kg or saline 1.2 ml/kg,30 minutes intervals.The first plantar incision was performed after the second fentanyl injection and the second incision was performed 14 days later.Paw withdrawal mechanical threshold(PWMT)and paw withdrawal latency(PWL)were measured at 24 hours preoperatively,2h,6h,D1,D3,D5,D7,and D14 postoperatively.We observed fentanyl-induced hyperalgesia priming in animal experiments.After the behavioral test,twenty-seven Sprageue-Dawley rats of the same specification were selected(n=9),and the same group was used to establish the same model.The rats were sacrificed on the 1st day after the first operation(D1),the 14 th day after the first operation(D14),and the 1st day after the second operation(2D1),respectively.L4-6 segments of spinal cord tissue were extracted according to different experimental methods.The levels of inflammatory factors(IL-Iβ、IL-6、TNF-α)in spinal cord tissues at different time(D1,D14 and 2D1)were detected by ELISA,p-p38 expression in spinal cord was detected by westernblot,and its relationship with microglia were detected by immunofluorescence assay.The mechanism of fentanyl-induced hyperalgesia priming was further investigated in animal experiments.In the second part of the experiment,eighteen Sprageue-Dawley rats were randomly divided into 3 groups(n=6): blank group(Control),incision+ fentanyl group(I+F),incision+fentanyl+dextrometheus group(I+F+Dex).The model of fentanyl-induced hyperalgesia priming was established by the same method.Fentanyl was injected subcutaneously four times at 60 μg/kg for 30 minutes intervals.Dexmedetomidine was injected intraperitoneally at 40 μg/kg 30 minutes before the first fentanyl injection.The PWMT and PWL were measured at the same time as in the first part,2h,6h,D1,D3,D5,D7,D14,2H2(2 hours after the second operation),2H6,2D1,2D3,2D5,2D7,2D14.The effects of dexmedetomidine by fentanyl-induced hyperalgesia priming were studied in animal experiments.After the behavioral test,twenty-seven Sprageue-Dawley rats(n=9)with the same specifications were assigned to the same group and the same model.The rats were sacrificed at D1,D14 and 2D1 and collected.The levels of inflammatory factors in the spinal cord were detected by ELISA,and p-p38 levels were detected by westernblot and immunofluorescence.To further explore the mechanism of dexmedetomidine in inhibiting fentanyl induced hyperalgesia priming.Results: 1.Fentanyl can induce hyperalgesia priming.2.Fentanyl increases the levels of inflammatory cytokines in spinal cord tissue.3.Dexmedetomidine inhibits fentanyl-induced hyperalgesia priming.4.Dexmedetomidine inhibits the levels of inflammatory cytokines in spinal cord tissue.5.Dexmedetomidine inhibits p-p38 expression in spinal microglia.Conclusion: Dexmedetomidine inhibits fentanyl-induced hyperalgesia priming by inhibiting the release of inflammatory cytokines in spinal cord and phosphorylation of p38 mitogen-activated protein kinase on microglia. |
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