Understanding the immunopharmacology of Morphine

Abstract

Morphine is a potent analgesic that has long been utilized in treating severe pain but poses significant risks, including addiction and various side effects such as dependence, respiratory depression, constipation, and immunosuppression. There are substantial research gaps concerning understanding the impact of morphine on the cells of the immune system. This thesis investigates morphine's effect on the immune system through four objectives to enhance understanding of its behavioral and immunological alterations. The first part of the study utilized a zebrafish model to examine the effects of morphine withdrawal, revealing pronounced behavioral changes, including increased movement patterns and reduced freezing behavior, indicating heightened anxiety and altered locomotion, and altered key genes involved in the addiction memory. In addition, morphine upregulated autophagy and inflammatory gene expression. Suggesting that neuroin flammation and induction of autophagy contribute to morphine addiction. This highlights the zebrafish as a valuable model for studying drug dependence. The second objective focused on morphine's immunosup pressive mechanisms, particularly its influence on macrophage polarization and functions. Our results in dicate that prior morphine exposure impairs the differentiation of bone marrow cells into macrophages and disrupts their polarization into the pro-inflammatory M1 and anti-inflammatory M2 phenotypes. This is evidenced by reduced expression of key markers CD80, CD86, CD40, MHCI, MHCII, iNOS, CD206, IL 10], altered morphology, and diminished phagocytic activity towards E. coli and Mycobacterium tubercu losis. The third part examined the mechanistic pathways by which morphine affects macrophage polariza tion and function, identifying the TLR-4 and autophagy pathways as critical mechanisms. Silencing TLR 4 and its pharmacological inhibition similarly disrupted macrophage polarization from M0 to M1 and im paired macrophage function. Further investigation revealed that morphine hindered antigen uptake by dysregulating autophagy. The final objective explored the potential for drug repurposing to mitigate mor phine addiction. Screening a library of FDA-approved medications identified three candidates—vi lazodone, indinavir, and lorazepam—with promising results for opioid receptor interactions. In summary, this study elucidates the multifaceted effects of morphine, ranging from behavioral alterations in zebrafish to the suppression of macrophage and dendritic cell function, along with the underlying molecular mecha nisms. Furthermore, these findings provide insights into potential therapeutic strategies for mitigating mor phine dependence. This comprehensive analysis emphasizes the necessity for continued exploration of mor phine's ramifications and the development of effective treatment strategies.