Dissertation
Central mechanisms of pain transmission
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.006931
Abstract
Chronic pain, broadly classified as inflammatory (caused by tissue damage) or neuropathic (caused by nerve damage), affects approximately 100 million Americans and only a minority of patients experience satisfactory pain relief with currently available pharmaceutics. The immune system plays a critical role in the pathogenesis of acute and chronic pain triggered by injury or illness. Here, I examine how the complement system, a principal component of the innate immune system affects pain signaling in the spinal cord. This is based on the accumulating evidence that complement, and particularly C5a/C5aR1 signaling, are important in the development and maintenance of neuropathic pain. Using a mouse model of neuropathic pain, I found that C5a signals via its receptor C5aR1 after injury, and that blockade of this signal can promote analgesia for mechanical hyperalgesia but not for cold allodynia. Furthermore, I found that microglia are responsible, in part, for this signaling by using a selective microglia knockout of C5aR1, and by demonstrating that microglia have clear cellular responses to C5a via C5aR1. I also evaluate the impact of C5a on projection neurons in the spinal dorsal horn and how nerve injury affects calcium signaling in the central terminals of the primary afferents.
Additionally, I examined how neuronal signaling changes with sensory perception altering decision making and motor movement, since one of the primary complaints of people with chronic pain is in how it can make them fearful to move affected limbs due to a fear of pain with movement. I found that mice demonstrate a clear preference for walking on innocuous tactile surfaces and that neuronal signals change based on sensation and motor movement.
In conclusion, I have demonstrated that C5a/C5aR1 signaling plays a critical role in the development and maintenance of chronic neuropathic pain in the spinal dorsal horn. I have also developed a method to integrate behavior and imaging in the context of pain while uncovering how a previously understudied brain region is impacted by both sensory qualities and motor movement.
Details
- Title: Subtitle
- Central mechanisms of pain transmission
- Creators
- Alex Keyes
- Contributors
- Yuriy Usachev (Advisor)Deniz Atasoy (Committee Member)Donna Hammond (Committee Member)Kathleen Sluka (Committee Member)Stefan Strack (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Summer 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006931
- Number of pages
- xvi, 186 pages
- Copyright
- Copyright 2023 Alex Keyes
- Language
- English
- Date submitted
- 07/25/2023
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 140-186).
- Public Abstract (ETD)
- Chronic pain affects 1 in 3 adults in the United States and only a minority of those people experience adequate pain relief from currently available medications. There are numerous causes and types of pain conditions, creating a significant complexity in understanding mechanisms that are driving pain, and in developing adequate behavioral models. Here, I examine how one component of the innate immune system, complement C5a, affects pain signaling in the spinal cord. Using a model of neuropathic pain, I found that C5a signals via its receptor C5aR1 after injury, and that blockade of this signal can promote pain relief for mechanical pain but not for cold pain. Furthermore, I found that microglia are responsible, in part, for this signaling by both blocking complement system on microglia, and by demonstrating that microglia have clear cellular responses to C5a via C5aR1. Additionally, I examine how neuronal signaling changes with sensory perception, altering decision making and motor movement, since one of the primary complaints of people with chronic pain is how it can make them fearful to move affected limbs due to a fear of pain with movement. I found that mice demonstrate a clear preference for walking on innocuous tactile surfaces and that neuronal signals change based on sensation and motor movement. In conclusion, I have demonstrated the role of C5a/C5aR1 signaling in the spinal dorsal horn, making it a feasible target for medications, and developed a method to integrate behavior and imaging in the context of pain.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984454433902771
Metrics
1 File views/ downloads
29 Record Views