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 these detrimental behavioral outcomes. Identifying the ability of ibudilast to reverse these protracted outcomes would provide a therapeutic framework for addressing the distinct adverse consequences experienced by Veterans with TBI who receive opioids for pain management in the rehabilitative period. Conti-1
Active duty and reserve service members are at an increased risk of sustaining a traumatic brain injury (TBI) compared to civilians due to combat-related activities. In addition, Veterans who sustain a TBI are more likely to receive treatment with opioid-based medications and engage in higher-risk opioid use patterns. Despite this disproportionate use of opioids for pain relief in brain injured Veterans, no studies have explored the long-term consequences of such treatment on TBI-related outcomes, such as behavioral responding to reward and pain stimuli. Therefore, the overall goal of this work is to develop useful rehabilitative strategies for reducing adverse functional outcomes related to addiction and pain in the delayed post-TBI period that are exacerbated with opioid-based pain management. This proposal seeks to accomplish this by identifying alterations in oxidative stress and inflammatory mediators and testing translationally-relevant therapies in an effort to reduce the burden of TBI-related deficits and improve the quality of life for Veterans suffering from TBI.
