MicroRNA-134-5p Modulates Distinct Pronociceptive Effects Between Remifentanil And Sufentanil

Opioids is the corestone for clinical anesthesia and analgesia.It is widely applied in the perioperative analgesic,neuropathic pain,and cancer pain management.With the steady growth of usage,some of its central side effects,including opioid induced hyperalgesia（OIH）,challenge its further popularization and application.Remifentanil is highly correlated to OIH,but another clinical commonly used opioids,sufentanil has rarely reported link with OIH,the different pronociceptive effects may help elucidate the development mechanism of OIH,find potential therapeutic targets,and guide clinical application.Micro RNA（miR）is a kind of short sequence non-coding RNA involved in post-transcriptional regulation of gene expression,and the content or function change of miR were shown to participate in pathological pain.miR is also associated with the synaptic structure remodelling and function activation underlying central sensitization during pain.μ-opioid receptor（MOR）is the main target of opioid drugs,and the key regulatory factors of OIH as well.T hus,we speculate that miR’s involvement in mediating spinal dorsal horn neural network proliferation and central sensitization via modulation of MOR is a possible mechanism for OIH.In this study,a mouse model of remifentanil or sufentanil hyperalgesia was established to investigate whether SDH miR-134-5p/MOR were related to distinct pronociceptive effects between them,and how the interaction between miR-134-5p and MOR regulated the change of synaptic morphology/function.This study provide a new idea for clinical prevention and treatment of OIH.ObjectiveTo compare the distinct pronociceptive effects between remifentanil and sufentanil;To explore the equivalent analgesic dose of remifentanil sufentanil;To evaluate the expression changes of SDH miR-134-5p and MOR in RIH/SIH mice;To investigate the effects of miR-134-5p on the behavioral changes in RIH and the expression of MOR in SDH by AgomiR-134 intrathecal injection;To investigate the effects of miR-134-5p on the behavioral changes in SIH and the expression of MOR in SDH by AntagomiR-134 intrathecal injection;To investigate the effects of MOR on behavioral in RIH mice and the expression of miR-134-5p by SDH MOR knockdown;To investigate the modulative effects of miR-134-5p/MOR on the dendritic spine remodeling and synaptic plasticity during OIH.ResultsⅠBoth remifentanil and sufentanil can dose-dependently induce hyperalgesia symptoms in mice,with calculated EC₅₀ are 10.66（10.06-11.17）and 9.03（8.23-10.01）μg/kg;3.14（2.78-3.59）and 2.72（2.42-3.11）μg/kg respectively.ⅡCompared to equivalent dose sufentanil,remifentanil is more easily cause long-time and severe hyperalgesia.Remifentanil can cause down-regulation of total/functional miR-134-5p expression in the spinal dorsal horn of mice and increase MOR expression.The equivalent dose of sufentanil had no such effect.ⅢOverexpression of miR-134-5p in the spinal cord can effectively relieve hyperalgesia symptoms of remifentanil.ⅣSelective reduction of miR-134-5p in the spinal cord can aggravate sufentanil induced hyperalgesia.ⅤKnockdown of MOR in spinal dorsal horn can prevent remifentanil induced hyperalgesia.ⅥUpregulation of miR-134-5p inhibited remifentanil-induced m EPSCs amplification.Abnormal proliferation of dendritic spines and synaptic remodeling induced by remifentanil were ameliorated by miR-134-5p overexpression.ConclusionmiR-134-5p/MOR pathway plays an important and unique role in distinct pronociceptive effects between sufentanil and remifentanil.Specifically,after remifentanil exposure,the expression and activity of miR-134-5p in the spinal dorsal horn decreased,induced the expression of downstream MOR,further accelerated dendritic spines reconstructing,synaptic structure reshape and synaptic plasticity;In contrast,sufentanil lacks the ability to down-regulate miR-134-5p.The activity changes of the miR-134-5p/MOR pathway may be an important reason for the high incidence of remifentanil hyperalgesia.