Endogenous opioid modulation of cortical pain circuits.

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary/Abstract Chronic pain is a pervasive burden affecting over 50 million US citizens. The experience of pain is subject to modulation based on context; however, the mechanism of this modulation is unknown. This project aims to unravel the intricate dynamics of prefrontal cortical microcircuits during expectation-driven endogenous pain relief, or placebo analgesia. Specifically, this research focuses on mu opioid receptor (MOR) expressing anterior cingulate cortex (ACC) neurons. This proposal integrates a preclinical placebo analgesia model in mice with cutting-edge techniques such as in vivo single-neuron resolution calcium imaging and the application of a novel opioid biosensor (δLight), to investigate the nuanced interplay between nociceptive signaling and the opioid system within the ACC during placebo analgesia. In Aim 1, viral expression of GCaMP8m under a MOR promoter (mMORp-GCaMP8m) enables visualization of nociceptive MOR+ neurons during placebo conditioning. In Aim 2, the role of enkephalin in the ACC during placebo analgesia will be investigated through CRISPR-mediated excision and biosensor-based monitoring. These aims strive not only to elucidate the neural correlates and potential mechanisms of placebo analgesia, but also to contribute to a broader understanding of how pain is endogenously regulated in a context-dependent manner by opioid systems in prefrontal cortex. As a pivotal component of this research endeavor, a training plan is outlined to foster the development of Ms. Oswell’s skills, preparing her for an independent research career. The successful execution of these aims not only contributes to the scientific understanding of placebo analgesia but also provides significant training opportunities, ensuring she is well-equipped with the requisite skills for a future independent research career. Through hands-on experience in state-of-the-art methodologies, she will acquire expertise that extends beyond the immediate scope of this project, cultivating a foundation for continued contributions to the broader field of pain neuroscience. The interdisciplinary nature of this research, combining molecular biology, neuroimaging, and behavioral analysis, provides a unique platform for skill diversification and the cultivation of a holistic research perspective. This project holds promise not only for advancing our understanding of pain modulation but also for shaping Ms. Oswell into a proficient and independent researcher poised to make substantial contributions to the scientific community.