Mechanisms underlying postoperative pain – A translational study
by Daniela Victoria Schmidt García
Date of Examination:2023-07-05
Date of issue:2024-02-05
Advisor:Dr. Manuela Schmidt
Referee:Dr. Manuela Schmidt
Referee:Prof. Dr. Thomas A. Bayer
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EnglishThe current focus on pain following surgery is in understanding the mechanisms behind it to develop methods to reduce its impact in patients. Surgery is necessary for treating several diseases and conditions; therefore, it is a relevant clinical problem worldwide. Untreated or poorly managed postoperative pain can lead to prolonged hospitalization, physical and psychological distress and impaired healing process for recovery. Moreover, untreated severe postoperative pain, it is associated with a higher risk of developing chronic pain. Effective acute pain management is important for preventing potential chronic illness and improving mobilization to return to normal life as soon as possible after a surgical procedure. Despite the fact that there is medication available for the postoperative period, it is still linked to unfavorable side effects due to the fact that they have been designed to target molecules with a more general function in the body. Understanding the mechanisms underlying postoperative pain is crucial for the advancement of new therapies in this context. This study highlights the importance of translational approaches for discoveries from basic research that can be applied in clinical settings. Certainly, animals are necessary to study the mechanisms involved in the generation of pain as they provide more possibilities for investigation than humans do. Yet, researchers must be aware of the similarities and differences between species at the moment of looking for new molecular targets. In this thesis, data-independent mass spectrometry was used for comparing the skin proteomes of established postoperative incisional pain models to determine shared proteins between humans and mice that have the potential to impact the pathophysiology of both species. The most regulated biological and molecular functions of these proteins were analyzed and compared. These comparisons showed some differences in the regulation of proteins in the overall proteome upon incision but shared conserved biological functions and cellular pathways in proteins with a strong regulation. Inflammation, enzymatic activity and metabolism were the most affected functions in humans and mice. Furthermore, 50 proteins were highly regulated upon skin incision in both models, resulting in interesting candidates for their validation in mechanisms associated with postsurgical pain. Three candidates were used for functional validation using isolated neurons involved in the transmission of pain signals. In addition, due to limitations in the method used for the identification of proteins, some relevant inflammatory mediators in the context of postoperative pain (e.g., cytokines) could not be detected. Therefore, an immunoassay approach was used to identify the inflammatory signature of the established animal model of incisional postoperative pain, detecting 13 cytokines and chemokines upregulated after surgical intervention. Remarkably, intracellular adhesion molecule 1, triggering receptor expressed on myeloid cells 1, and interleukin 16, three poorly described cytokines in the context of pain, showed an increase in the activity of the transient receptor ankyrin 1, an important channel in the physiology and pathophysiology of pain perception, suggesting that these cytokines may be involved in pain signaling following incisional surgery.
Keywords: postoperative pain, post-surgical pain, incisional pain, acute pain, chronic pain, pain proteome