Sunday, April 28, 2024
4/28/2024
PROJECT SUMMARY Chronic pain affects nearly 1 in every 5 adults worldwide1, posing a major public health concern and economic burden. Yet, despite the widespread prevalence of chronic pain, few effective strategies for long-term pain management exist. Historically, physicians have relied upon a cocktail of analgesics, including tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and opiates, to treat persistent symptoms in chronic pain patients54. However, this approach carries significant risks – reliance upon prescription opioids has fueled the opioid abuse epidemic that has crippled the United States for the past two decades, and long- term use of opioids has conversely been shown to increase pain sensitivity over time, necessitating larger and larger doses to achieve analgesic efficacy53. Therefore, to successfully combat the opioid epidemic, we must investigate underlying mechanisms of pain chronification in pursuit of novel, non-addictive pain interventions. Until recently, much of the pain field has focused on peripheral nervous system and spinal cord circuit dysfunction, which primarily influence the somatosensory elements of chronic pain. Chronic pain, however, is more than purely a sensory phenomenon; patients also suffer from the “unpleasantness” or negative valence associated with pain22. Recent work from our collaborators has identified a specific ensemble of neurons within the basolateral amygdala (BLA) that encodes for the negative valence of pain22. However, it remains unknown how activity within these nociceptive BLA neurons and the circuits in which they are embedded are altered post-injury, and whether these changes contribute to pain chronification. Using an innovative activity-based rabies screen pioneered by our lab28 in parallel with an unbiased whole-brain c-Fos activity mapping approach, we can generate a list of input regions to the BLA whose activity is elevated exclusively during chronic pain. To test the functional contribution of these input circuits in pain chronification, we will perform chemogenetic inhibition studies in tandem with classical pain assays. By identifying brain-wide, circuit-level changes that occur post-injury to promote chronic pain, we will elucidate key brain regions and circuit targets that will enable the development of non-opiate therapies for mitigating chronic pain.
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