Investigating the Effects of Spinal Cord Injury and Rehabilitative Training on Corticospinal Circuits Controlling Contextual Opioid Analgesic Tolerance

Yale University, New Haven CT

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Abstract

PROJECT SUMMARY: Pain remains a major issue after spinal cord injury (SCI), with over 60% experiencing chronic pain and one-third suffering from intense, opioid-resistant pain. This leads to higher opioid use, increasing risks of tolerance and misuse, underscoring the need to understand the biological factors involved. As individuals with SCI increase their opioid intake, they may develop tolerance to the analgesic effects of these drugs in particular contexts. This contextual tolerance can be reversed when the drug is used in a different context. Because contextual tolerance can lead to increased use, it raises the risk of opioid use disorder and fatal overdose. Understanding the neuronal mechanisms behind associative analgesic tolerance will help develop new treatments to manage pain while reducing opioid use and overdoses. Few studies have examined the biological factors that influence contextual tolerance, and no research has explored the effects of SCI and rehabilitative training, a key therapy for SCI patients, on environmental control of opioid tolerance. This proposal aims to address this knowledge gap. Using a novel behavioral training paradigm in mice, I identified brain regions activated by tolerance. The anterior cingulate cortex (ACC) plays a crucial role in contextual learning, nociception, and opioid analgesia, which are aspects of contextual tolerance. My preliminary data suggest that contextual tolerance leads to the formation of a tolerance-active neuronal ensemble in the ACC. Preliminary studies using chemogenetic approaches indicate that the ACC is necessary and sufficient for the expression of contextual tolerance. Thus, these data indicate that the ACC may function as an orchestrator of contextual tolerance. The ACC projects directly to the spinal cord (SC), and injuries that induce neuropathic pain, such as SCI, increase the excitability of this circuit, leading to hyperalgesia. I hypothesize that the ability of opioids and environmental factors to regulate ACC to SC circuit activity and induce contextual tolerance is impaired after SCI, and that this effect can be reversed through rehabilitative therapy. I will test this hypothesis using corticospinal tracing, SCI, and rehabilitative training models combined with contextual tolerance conditioning and immunohistochemistry in mice. I anticipate that SCI will induce a tolerance-like effect in mice that will occlude control of tolerance. I also predict that rehabilitation will restore contextual tolerance and rescue SCI-induced changes in neuronal activity in the ACC to SC circuit. In addition to significant scientific advances in understanding how injury affects the neural substrates responsible for controlling analgesic tolerance, this supplement proposal will provide me with advanced training to improve my technical and academic skills, laying the groundwork for my career as an independent researcher in my research laboratory. During the training phase, I will gain extensive training in corticospinal circuit tracing, spinal contusion, pain assays, and rehabilitative motor therapy. This training, combined with my expertise in behavioral pharmacology and addiction models, will create a strong foundation for competitive grant applications and support my transition to becoming an independent investigator as an Assistant Professor.