Mechanisms underlying chronic pelvic pain associated with endometriosis

Author: Jessica Maddern

  • Thesis download: available for open access on 16 Aug 2023.

Maddern, Jessica, 2022 Mechanisms underlying chronic pelvic pain associated with endometriosis, Flinders University, College of Medicine and Public Health

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Abstract

Endometriosis is a chronic and debilitating gynaecological condition which affects 10% of reproductive aged women. Chronic pelvic pain (CPP) is a cardinal symptom of endometriosis, with many patients experiencing widespread pain, or being co-diagnosed with visceral comorbidities associated with chronic pain. Unfortunately, little progress has been made in understanding the mechanisms that contribute to CPP in endometriosis, and as such, therapeutic treatments are lacking. Unfortunately, a major limiting factor in the development of treatments for CPP in endometriosis is the lack of translatable research originating from effective pre-clinical animal models. To this end, the work presented in this thesis focuses on pain in endometriosis with the primary aim to advance pre-clinical models of endometriosis and specifically utilize them for the study of CPP mechanisms.

This thesis starts by exploring the current literature surrounding endometriosis, covering disease pathogenesis and diagnosis, current treatments, and details currently suggested mechanisms of CPP development in endometriosis. By doing this, we highlight the unmet clinical need in successful treatment of CPP in endometriosis and emphasize the importance of pre-clinical models in elucidating mechanisms to identify key therapeutic targets.

From here, we present our original contribution to the field, aimed at investigating the mechanisms of CPP development in endometriosis. In Chapters 2 and 3, we establish two pre-clinical models of endometriosis in mice. Specifically, we further characterise the chronic development of endometriosis and use multiple in vivo approaches to investigate the development of widespread CPP. By presenting indications of both spontaneous and evoked ‘pain like’ behaviours across visceral organs commonly associated with endometriosis comorbidities, including the bladder, colon, and vagina, we position these pre-clinical models of endometriosis for the study of CPP mechanisms associated with this disease.

To investigate how CPP develops in these models, we first must understand how pain is signalled from visceral organs affected by endometriosis in normal/healthy animals. Chapter 4 aims to bridge this knowledge gap by investigating how normal and nociceptive stimuli are sensed by sensory nerves within the female reproductive tract. Making use of pharmacological modulators and specialised in vivo, ex vivo and in vitro techniques, we study the function of voltage gated sodium channels (NaV) expressed in vaginal-innervating sensory neurons and demonstrate the role they play in regulating vaginal nociception.

Building on this new knowledge in pain signalling in healthy animals, we use our mouse model of endometriosis and CPP to link these concepts in Chapter 5. In this chapter, we successfully utilise our endometriosis mouse model to explore alterations in vaginal sensory signalling.Specifically, we investigate a role of the NaV channel subtype, NaV 1.7, in the development of enhanced vaginal pain in endometriosis.

Finally, in Chapter 6, we employ live-cell calcium imaging to explore a direct role of the peritoneal fluid in aberrant pain associated with endometriosis. Bridging the gap between our pre-clinical model and the clinic, we utilise peritoneal fluid samples collected from both mice and women with endometriosis and CPP.

Published peer-reviewed papers have been included in this thesis, in which Jessica Maddern is primary author. An author contribution statement is listed at the beginning of each relevant chapter.

Keywords: endometriosis, pre-clinical mouse model, chronic pelvic pain

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: Professor Stuart Brierley