Of the more than 300,000 service men and women that have sustained traumatic brain injury (TBI) due to recent conflicts, 70-80% are treated for pain. Those TBI-injured Veterans that are provided pain management are more likely to receive opioid-based treatment and engage in higher-risk opioid use. This increase in prescription opioid use among Veterans with TBI reflects the nationwide opioid abuse and dependence crisis and highlights the need to understand the long-term, progressive deficits, such as those related to reward and pain outcomes, that may selectively and disproportionately occur in TBI patients given post-injury opioid therapy. The exact mechanism(s) underlying a synergy among TBI and early opioid exposure are unknown, but recent data indicating the prototypical opioid therapeutic, morphine, leads to activation of reactive oxidative species (ROS) and pro-inflammatory mediators opens the possibility it could enhance or extend the induction of these systems following TBI, worsening pathological pain for which opioids were intended to alleviate, as well as contributing to addiction vulnerability. [The preliminary data presented in the application support this suggestion, as morphine exposure following experimental TBI resulted in synergistic elevations in cortical levels of ROS and the pro-inflammatory cytokine, interleukin 1 beta, over that observed with either condition alone in the acute post-injury phase (7 days post-TBI), and was associated with increased microglial expression in the cortex at more protracted timepoints (30 days post-TBI).] These data warrant further investigation of the additive effects of TBI and subchronic opioid exposure on long-term TBI outcomes, as well as indicate that modulators of neuroimmune function, such as the glial attenuator ibudilast, could prevent or reverse these processes and associated behavioral deficits. [The central hypothesis of this proposal is that morphine exposure following TBI will heighten injury-induced alterations in reward, pain and their interaction through exacerbated recruitment of oxidative and inflammatory systems in regions responsible for these behaviors, and that these will be reversed by neurotherapeutic intervention with a glial attenuator, ibudilast. This hypothesis will be interrogated with three Specific Aims: (1) Evaluate the long-term impact of TBI on integrated pain and reward responses and the ability of post-injury morphine to potentiate these outcomes. (2) Assess glial attenuation with ibudilast to ameliorate TBI-induced pain and reward responses augmented with post-injury morphine. (3) Quantify the influence of post-injury morphine on TBI-induced oxidative stress and neuroinflammation, and the efficacy of ibudilast to attenuate these outcomes, in neural reward and pain centers.] This work would establish that morphine acutely after TBI exacerbates injury-induced oxidative stress and inflammatory responses in regions mediating reward and pain affect, potentiating ...