Harnessing cortical neuromodulation to disrupt pain perception

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PROJECT SUMMARY Chronic pain is characterized by sensory, emotional, and cognitive dysfunction. Some patients on opioid therapies can perceive the negative valence of pain as separate, or “dissociated,” from the sensation of pain. This suggests that altering the affective-attention dimension of pain contributes significantly to the therapeutic effect of opioids. However, opioids have significant negative side effects. Opioids carry addictive and respiratory depression liabilities due to the expression of mu opioid receptors (MORs)—the molecular receptor binding opiates—in reward-related and brainstem breathing areas of the brain. Identifying the nociceptive brain circuits underlying opioid analgesia, separate from those underlying dangerous side effects, is key to developing improved, non-addictive therapeutics for managing chronic pain and combating the Opioid Epidemic. Many brain regions contribute to the emotional and cognitive facets of pain. Importantly, anticipation of pain, acute noxious stimuli, and chronic pain all strongly activate the anterior cingulate cortex (ACC). The function of the ACC in pain processing appears to integrate nociceptive information within working memory to direct attention to and facilitate anticipation of nociceptive stimuli, but it remains unknown how noxious information enters the ACC. In the DP2 parent award, we are currently exploring nociceptive inputs from the amygdala, however, there are other key connective routes of pain-related information into the ACC, such as the midline thalamus (MTh). Here, we extend the parent DP2 studies to investigate the MOR+ MTh projection circuit that innervates nociceptive ACC regions. In Goal 1, we will determine the neuroanatomy of opioidergic nociceptive neural circuits using activity-dependent viral and mouse genetics, and in Goal 2 we will determine the functional role of thalamocortical opioidergic circuits to pain behavior using cell-type specific manipulations and machine- vision based behavior quantification methods, which were developed in the parent DP2 experiments. Completion of the proposed research will facilitate the trainee’s technical mastery of several advanced neuroscience technologies, data analysis and statistics, as well as several training goals to prepare the trainee for a career in pain neurobiology research.