Modulating pain through cortical endogenous opioid circuits

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PROJECT SUMMARY Pain is essential to life, serving a vital protective role by directing attention to acute injury or the threatening source of pain. However, unrelenting chronic pain demands unrelenting attention, preventing attendance to other goal-oriented behaviors and reducing quality of life. Chronic pain is characterized by sensory, emotional, and cognitive dysfunction. Opioids, the current standard of care for chronic pain, have a high addictive liability and their misuse can induce respiratory depression and death. This highlights a critical need for improved pain treatment. Interestingly, some chronic pain patients on opioid therapy can perceive pain dissociated from its negative valence, suggesting that alleviation of emotional – or affective – and cognitive symptoms predominantly underlie the analgesic effect of opioids. The research goal of the proposed project is to characterize a novel pain-active subcortical-cortical circuit that selectively contributes to affective-attention pain behaviors, and to determine its overlap with the endogenous mu opioid receptor (µOR) system. The anterior cingulate cortex (ACC), an area known for its involvement in pain perception, emotion, and cognition, plays an executive role in directing attention towards pain. Additionally, opiate analgesic mechanisms resulting from µOR activation are partly localized to the ACC. The ACC receives input from the basolateral amygdala (BLA), which contains a pain- affect valence ensemble required for attending to pain. However, it is unknown if BLA pain-affect valence information is processed in the ACC, or if opioid signaling in the ACC can disrupt this BLA pain-affect input to reduce the perceived negative valence of pain. Aim 1 will determine the necessity and sufficiency of nociception- active BLA (BLAnoci) inputs to ACC in driving pain affective-attention behavior with an in vivo optogenetic approach. In compliment, the synaptic connectivity of BLAnoci inputs to the ACC will be characterized using optogenetic-guided ex vivo slice electrophysiology. Aim 2 will test the necessity and sufficiency of µOR- expressing, nociception-active ACC neurons to reverse chronic pain-impaired affective-attention behavior. The use of opiates to treat the immense emotional and cognitive demand induced by chronic pain facilitates the ongoing Opioid Epidemic. Targeting cortical opioid receptors and nociception-active circuits to selectively lessen the emotional component of pain could be an effective treatment, achieving the long-term objective of this research to identify non-addictive therapies for chronic pain. Completion of this fellowship will achieve the training goals of expanding the experimental expertise of Dr. McCall and establishing her as an expert in the emerging field of pain affect.