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Chronic Pain in a Mouse Model of Multiple Sclerosis: Contributions of the Kappa Opioid System
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- Author / Creator
- Chadwick, Caylin Isabelle
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The perception of pain is a multimodal experience that is encoded by regions of the central nervous system (CNS) that are involved in sensation, affect, and cognition. Chronic pain is not merely the persistence of pain, but a debilitating condition that is associated with neurochemical dysregulation in these regions. In the general population, chronic pain affects approximately 1 in 5 Canadians, but people living with multiple sclerosis (MS) experience chronic pain at a 3x higher rate. Despite this extremely high prevalence, our understanding of the root cause of chronic pain in MS is very limited. In the general chronic pain field, the kappa opioid system is emerging as an important regulator of the CNS regions involved in the sensory, affective, and cognitive components of pain. The goal of this thesis was to evaluate whether changes in the kappa opioid system occur in these regions in a mouse model of MS by probing the in vivo function of exogenous kappa opioid receptor (KOR) agonism and by analyzing post-mortem CNS tissue for mRNA and protein expression of the KOR and its endogenous ligand, dynorphin. To test this, I induced male and female C57Bl/6 mice with experimental autoimmune encephalomyelitis (EAE), an established mouse model of MS. This model results in progressive ascending motor impairment 1-2 weeks post-induction, with symptoms of pain hypersensitivity beginning a few days prior. KOR agonism has recently been implicated in remyelination, but I was able to confirm that daily KOR agonism did not alter EAE severity and therefore did not confound the behavioural results. At onset of motor symptoms (characterized by a weak tail), EAE caused mechanical allodynia, characterized by a lowered paw withdrawal threshold. Systemic KOR agonism (1.6-30 mg/kg, i.p.) produced robust analgesia in both control and EAE mice. However, direct intrathecal injection of a KOR agonist (10 ug) failed to produce analgesia in EAE mice. I also showed that KOR-induced aversion (10mg/kg, i.p.) was blunted in EAE mice. Following behavioural assessment, I measured KOR and dynorphin mRNA and protein expression in the following CNS regions involved in the three aspects of pain: the spinal cord (sensory), nucleus accumbens (NAc; affective), amygdala (affective), and claustrum (cognitive). I found that KOR mRNA and protein expression was downregulated in the spinal cord of EAE mice, KOR protein expression was upregulated in the NAc of EAE mice, and the mRNA of dynorphin’s precursor was downregulated in the claustrum of EAE mice. Overall, this thesis has confirmed that the kappa opioid system is dysregulated in a mouse model of MS within CNS regions associated with the sensory, affective, and cognitive components of pain. These finding are in line with current chronic pain literature and highlight the importance of bridging the literature gap between the kappa opioid system, chronic pain, and MS. Future research should focus on investigating the nature of the relationship between kappa opioid system dysregulation and MS-induced chronic pain. Knowing whether this dysregulation is a symptom or a cause of MS-induced chronic pain will guide future development of pain therapeutics for people living with MS. -
- Graduation date
- Fall 2021
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.