Mechanism Of Action Of The G Protein-coupled Receptor Biased Agonist TRV130 In Hypersensitivity And Tolerance

Opioids are currently the most effective analgesics for treating severe pain,but their long-term use is limited by adverse effects.In order to develop novel analgesics with analgesic effects and to alleviate the side effects associated with opioids,G protein-coupled receptor-biased agonists have become a focus of research.The aim of this study was to investigate the analgesic effects and hyperalgesia and tolerance of the G protein-coupled receptor bias agonist TRV130 and to further investigate the mechanisms by which TRV130 produces hyperalgesia and tolerance through molecular experiments.This experiment used non-nerve-injured mice and mice establishing a preserved nerve injury(SNI)model.The analgesic effects and hyperalgesia and tolerance produced by intrathecal injection of TRV130 and morphine were determined using the von Frey assay.The extent of activation of microglia by TRV130 and morphine and the effect on the expression of inflammatory factors in the mouse spinal cord were assessed in vivo by molecular biology.The modulation of the activation of BV2 cell and primary microglia by TRV130 and morphine,administered alone and after LPS induction,was assessed in vitro.The results of this study showed that:(1)Intrathecal injection of TRV130 had a dose-dependent analgesic effect,and its analgesic effect was weaker than that of morphine at the same dose.(2)Intrathecal injection of TRV130 induced a dosedependent hyperalgesia and tolerance,which were both weaker than morphine at the same dose.(3)Intrathecal TRV130 activates spinal microglia and promotes the expression of inflammatory factors,but its activating and promoting effects are weaker than those of morphine.(4)TRV130 alone did not promote upregulation of inflammatory factor expression in BV2 cell line and primary microglia,but it promoted further upregulation of LPS-induced inflammatory factor expression,and its promotion effect was weaker than that of morphine.This study demonstrates that TRV130,similar to morphine,induces hyperalgesia and tolerance,activates spinal microglia and promotes the upregulation of inflammatory factor expression.However,the hyperalgesia and tolerance induced by TRV130 and the activation of microglia were weaker than that of morphine.These results further clarify the role of microglia in hyperalgesia and tolerance,suggest the value of TRV130 in clinical applications,and provide a reference for the development of G protein-coupled receptor-biased agonists.