Persistent pain is common and debilitating. Long after apparent remission of the pain initiated by the primary insult, some patients experience relapse and recurrent episodes of severe pain. The long-term goal of this project is to decipher mechanisms that regulate the balance between remission and relapse of pain. Understanding these mechanisms will help to identify new therapeutic strategies to prevent the transition from acute to chronic pain and reduce the use of opioid for treatment of pain. We have developed a new mouse model to study the remission and relapse of pain. After a primary insult (surgical incision or a short dose of chemotherapy), a short period of pain (acute pain) is followed by remission in which pain sensitivity is absent. However, during remission pain can be reinstated by inhibition of anti-inflammatory cytokine or opioid receptor signaling, neither of which affect pain sensitivity in naive animals. Our preliminary data show that interleukin (IL)-10 is permanently upregulated during remission from pain and keeps neuroinflammation silent and upregulates δ-opioid receptor (δOR) gene expression and analgesic effects. This suggests that remission is a sensitized state that results from long-term neuroplasticity in the nociceptive system, which if inhibited will trigger relapse of pain. Our long-term goal is to switch transient remission to permanent recovery. Towards this goal, the central hypothesis of our proposal is that persistent IL-10 signaling is necessary to prevent the relapse to pain by keeping neuroinflammation silent and facilitating the activation of the endogenous opioid system. Thus, we will test this hypothesis with 2 specific aims. Our first aim will test the hypothesis that IL-10 signaling acts as a “brake” to keep neuroinflammation latent and prevents relapse to pain. Our second aim will investigate the hypothesis that relapse is prevented because IL-10 signaling promotes upregulation of gene expression and functional activation of δOR in the DRG. This proposal will fill critical gaps of knowledge on the roles of neuroimmune and immune-opioid crosstalk in chronic pain. Because regulation of the remission and relapse of pain has not been investigated previously, our model of pain recurrence can transform our knowledge on long lasting nociceptive plasticity in chronic pain. Ultimately, it could transform clinical practices by treating patients in remission to prevent the relapse of pain.