Distinct amygdalar neural circuits for pain and opioid dependence

About This Grant

PROJECT SUMMARY / ABSTRACT │ Despite the rapid increase in Opioid Use Disorder (OUD), opioids remain effective for managing postoperative and moderate-to-severe pain. However, prolonged opioid use can lead to dependence, severe withdrawal syndrome, and opioid-induced hyperalgesia (OIH). These side effects increase patients' reliance on opioids, complicating their long-term clinical use. The impact of opioid dependence on specific brain circuits remains poorly understood. Chronic opioid exposure induces adaptive processes that counteract the cellular effects of MOR signaling, resulting in hyperexcitability of affected cells. Understanding the susceptibility of specific neural circuits to opioid-induced plasticity is crucial for disentangling the neural substrates of opioid dependence effects. MORs are densely expressed in the ascending parabrachio-amygdalar pathway, a critical pain and threat-related circuit initiating defensive responses. MORs are found on glutamatergic neurons in the external lateral parabrachial nucleus (PBNMOR) that project to the central amygdala capsule (CeC). Increased activity in PBN→CeC projections potentiates rodents' defensive responses to pain and anxiogenic stimuli, suggesting that the PBNMOR→CeC circuit may be particularly vulnerable to hyperexcitability following opioid dependence. Whether hyperexcitability in this circuit contributes to opioid dependence behaviors is unknown. To address these knowledge gaps, we will leverage a mouse model of fentanyl dependence compatible with a postoperative pain model, utilizing in vivo calcium imaging, single-nuclei RNA sequencing, and functional neural circuit manipulations. We found that fentanyl-exposed animals display hyperalgesia and withdrawal behaviors. Fentanyl withdrawal robustly activates the PBNMOR and anterior CeC, particularly in neurons expressing Protein Kinase C δ (CeCPKCδ). These neurons drive defensive responses to pain and receive direct glutamatergic input from the PBN. RNA sequencing suggests multiple subpopulations of CeCPKCδ that might differentially engage nociceptive processes versus dependence within distinct CeC subregions. We will test the hypothesis that hyperexcitability in the PBNMOR and CeCPKCδ connections may drive aversive signaling and learning during fentanyl dependence and recovery from post-surgical pain. Completion of these aims will allow us to pinpoint the microcircuit identities of cells involved in pain and dependence, helping to understand the impact of chronic opioid exposure on the PBNMOR→CeCPKCδ circuits and their influence on postoperative pain.