Opioids have been used for treated pain for thousands of years.Meanwhile, opioids induce drug addiction, which causes serious medical and social problems.Most opioids research have been concentrated on neurons in the central nerve system (CNS) , however, the action of glia, which accounts for 90% cells in CNS, have been long neglected.Unlike the classical opioidneuron stereoselective interaction, opioids were found to nonstereoselectively bind the accessory protein myeloid differentiation factor 2 (MD2) of innate immune ToⅡlike receptor 4(TLR4), which induces glial activation and proinflammatory factors production, therefore contributing to opioid hyperanalgesia, drug tolerance, dependence and addiction.A series of TLR4 antagonists have been discovered by multiple drug discovery strategies for inhibiting the opioids side effects and treating drug abuse, among which(+)naltrexone and T5342126 have been transferred to Xalud and BioLineRx respectively, for further preclinical/clinical drug development.