Exploring the role of sex differences in chronic pain

• Author / Creator

  Mifflin, Katherine A

• Sex traditionally has been an understudied variable in the chronic pain literature. However, more recent research has begun to explore the role of sex in the etiology of chronic pain. The present thesis adds to the current literature by expanding on research demonstrating the significant effect of sex in two models of chronic pain. Furthermore, the results of this thesis outline how potential treatment for chronic pain may have different effects in males and females.
  In Chapter 1 the role of sex in the formalin model of chronic inflammatory pain was explored. In this chapter, I demonstrate that while both male and female mice exhibit similar nociceptive behaviour in the formalin model, they respond differently to treatment with the monoamine oxidase inhibitor phenelzine and its metabolite PEH. Both drugs reduced nociception, but only in male mice. I found that pharmacological manipulation of the levels of serotonin, noradrenaline, and gamma-aminobutyric acid (GABA) revealed a serotonergic dependent nociceptive pathway in male mice and a more GABAergic dependent pathway in female mice.
  In Chapters 2-4 I began to explore the benefits of a nonpharmacological intervention in Multiple Sclerosis (MS). Here again significant sex differences were found. Daily voluntary wheel running in the experimental autoimmune encephalomyelitis (EAE) model significantly improved disease scores in male but not female mice (Chapter 2). Improved disease scores in males with EAE who ran were associated with less axonal damage and oxidative stress at the chronic stage. Furthermore, voluntary wheel running also had effects in the brain in chronic EAE. I found that voluntary wheel running could modulate levels of neuroactive steroids associated with the EAE (Chapter 3). Female mice with EAE who ran had significantly increased levels of brain pregnenolone compared to male EAE mice who ran. In contrast, male mice with EAE had significantly higher levels of brain allopregnanolone compared to female mice with EAE regardless of exercise. Allopregnanolone can be neuroprotective and therefore may account for the beneficial effects of running in male mice.
  
  Finally, I explored the effect of voluntary wheel running and sex on nociceptive behavior in male and female mice with EAE. While chronic pain is a well-established secondary symptom of MS, few treatments or interventions exist to manage pain in the disease. I therefore wanted to explore whether voluntary wheel running could affect nociceptive behavior in male and female mice with EAE at the onset of disease. Interestingly, I found that daily voluntary wheel running reduced nociceptive behavior only in female mice with EAE (Chapter 4). I went on to show that this sex difference is due to different levels of pain-related circulating cytokines in the periphery and differences in dorsal root ganglia excitability between the sexes. Overall, my experiments demonstrate that male mice have a more pro-inflammatory profile when given access to a running wheel that ultimately contributes to their nociceptive behavior in the disease.
  In summary, my work demonstrates the value of including sex as a variable in chronic pain research. In addition, it highlights how sex is an extremely important variable to consider when exploring both pharmacological and non-pharmacological interventions for chronic pain. Inclusion of variables such as sex in pre-clinical studies will ultimately lead to better translation of research and treatment for patients.

• Subjects / Keywords

  • multiple sclerosis
  • exercise
  • sex differences
  • chronic pain
  • formalin

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R33776B2S

• License

  Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.