UC Irvine

The opioid epidemic, fueled by the over prescription of opioid analgesics, necessitates innovative strategies to enhance the efficacy of opioid therapy while mitigating its adverse effects. This dissertation investigates the potential of Corydalis yanhusuo extract (YHS) and GPR 139 in addressing opioid-related challenges. Chapter 1 provides a comprehensive overview of the opioid epidemic, emphasizing the need for alternative approaches to opioid therapy. In Chapter 2, we delve into the multifaceted impact of YHS on morphine antinociception, showcasing its potential to enhance the efficacy of morphine and consequently reduce opioid dependence. Our findings reveal that the coadministration of YHS with morphine not only hinders the development of morphine tolerance, dependence, and addiction but also demonstrates a remarkable capacity to reverse morphine dependence and addiction in animals subjected to extended morphine treatments. These results collectively suggest the potential utility of YHS as a co-medication in morphine therapies, offering a promising avenue to mitigate adverse morphine effects. Chapter 3 delves into the molecular mechanisms underlying YHS's ability to reduce morphine tolerance. By exploring the modulation of mu opioid receptor (MOR) expression in various brain regions, including the lateral septal nucleus, primary and secondary motor cortex, anterior cingulate cortex, and thalamus, the study aims to elucidate the potential of YHS in preventing tolerance development.

Chapter 4 explores the bioactive constituents of YHS, focusing on those with the capability to inhibit the development of morphine tolerance. Using reverse phase high-performance liquid chromatography (HPLC) and tolerance assays, the study aims to identify the active compounds responsible for YHS's mitigating effects on morphine tolerance, laying the groundwork for targeted interventions in pain management.

Chapter 5 explores the multifaceted role of GPR 139, a receptor discreetly expressed in the medial habenula, in modulating neurobehavioral circuits. The study systematically evaluates the potential of the GPR 139 agonist, JNJ-63533054, as a versatile pharmacological agent. The focus lies on its multifaceted attributes, particularly its remarkable ability to inhibit morphine-induced analgesia and self-administration. This suggests a promising avenue for JNJ-63533054 as an analgesic, showcasing its potential in pain management and its potential to modulate opioid-related behaviors. The findings underscore the versatility of JNJ-63533054, positioning it as a candidate with dual implications, both in mitigating pain responses and potentially addressing concerns related to opioid misuse and addiction. In addition, this chapter investigates the interaction between YHS and GPR 139 in blocking morphine tolerance. By elucidating whether GPR 139 is involved in the mechanism by which YHS mitigates morphine tolerance, the study provides insights into alternative pathways for targeting pain medications. In conclusion, this dissertation presents a comprehensive investigation into the potential of YHS and morphine as co-medications in opioid therapy. These findings offer promising avenues for developing alternative strategies to address the opioid epidemic and improve pain management.