| The international association for the Study of Pain defines neuropathic pain as "pain caused by somatosensory nervous system diseases or diseases".Long term neuropathic pain has brought serious burden to both the body and spirit of patients.Up to now,the treatment of chronic neuropathic pain is still mainly drug therapy,but the conventional therapeutic drugs can not meet this purpose obviously.As the gold standard for treating many types of pain,μ opioid drugs have serious side effects that limit their use,making it necessary to find a new treatment strategy.δ opioid receptor agonists are receiving increasing attention in clinical practice due to their good analgesic effects and fewer side effects.In this study,δ opioid agonist was used in combination with μ opioid drugs to investigate its inhibitory effect on hyperalgesia,and whether this effect is related to the inhibition of microglia and NLRP3 inflammasome activation.In this study,partial sciatic nerve ligation(PSNL)was used as a pain model.The mechanical threshold of the surgical side was reduced after modeling significantly,and maintained at a relatively stable level within 14 days after operation,which imitated the clinical chronic neuropathic pain caused by various reasons.Different concentrations of δ-opioid receptor agonist SNC80 and μ-opioid receptor drug morphine were injected intrathecally to investigate their analgesic and antihyperalgesia effects in PSNL model.The results showed that SNC80 could enhance the acute analgesic effect of low concentration morphine and reduce the side effects of morphine such as hyperalgesia and tolerance.We further explored the mechanism of this effect,and found that SNC80 did not increase the level of microglia in the spinal cord,and the combination group had significantly lower proinflammatory activation markers of microglia and activation of NLRP3 inflammasome than the morphine treatment group.These results suggest that SNC80 may enhance the analgesic effect and improve hyperalgesia by affecting the proinflammatory activation of microglia.Molecular experiments of BV2 and primary microglia cells suggested that NF-κB/NLRP3 pathway may be involved in the regulation of SNC80 on microglia.The present study found that SNC80,a δ-opioid receptor agonist,could significantly improve the side effects of μ-opioids drugs,such as hyperalgesia and analgesia tolerance.Indicating that side effects originating from MOR can be alleviated by simultaneously activating DOR. |
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