SCI-Induced Chronic Pain is Driven by a Central to Peripheral IL-1 Mediated Signaling Pathway

Up to 80% of spinal cord injury (SCI) patients develop chronic pain, with the majority of that pain emanating from somatic regions below the level of injury. Below-level neuropathic pain is rated as being severe and is notoriously difficult to manage because the mechanisms responsible for its development and persistence are not well-understood. Research suggests that the sequelae of signaling events that are engaged at or near the time of injury significantly contribute to pain chronicity. Research has also shown that interleukin-1β (IL-1β) is released from the site of SCI within hours of injury, but there is still a significant gap in our knowledge of its role in the development of chronic SCI pain. Recent whole transcriptome RNA sequencing performed by our laboratory has shown that IL-1β mRNA (Il1b) is increased in the spinal cord and dorsal root ganglia (DRG) at the level of injury, while mRNA for its receptor, IL-1R1 (Il1r1) is increased in the spinal cord and DRG below the level of injury, suggesting that SCI causes the emergence of a central to peripheral IL-1β-dependent signaling pathway that contributes to the development and persistence of chronic SCI pain. To further explore the peripheral component of this pathway, we measured levels of IL-1α, IL-1β, and IL-1R1 in glabrous and hairy skin for 7 days following SCI. The RNAseq data shows that the expression of IL-1 family of cytokines, particularly IL-1β, was highly enriched at 1 day post injury in the SC and DRG at the level of injury but not below. Expression of the receptor IL-1R1 was greatly enriched in SC and DRG below the level of injury. The ELISA data for the SC and DRG matched the expression data from RNAseq. Interestingly, analysis of IL-1β and IL-1α content in the hairy and glabrous skin changed significantly from their naïve counterparts. For IL-1β, protein content was increased in the glabrous skin 1 day post injury, but showed no significant change hairy skin. IL-1α showed an inverse effect, with hairy skin showing a significant increase as early as 3 hours post injury before returning to naïve levels at day 3. Preliminary staining of SC below the level of injury confirmed RNAseq data for the expression for the receptor IL-1R1, with a notable increase in IL-1R1 expressing cells. This data indicates that activation of IL-1β, and perhaps IL-1α, contributes to inflammatory responses after injury and may contribute to sensitization of nociceptors below the level of injury. Additionally, including IL-1α, whose mechanisms and functional roles are poorly understood, introduces a potential novel therapeutic target in addition to IL-1β. Future research is focusing on the role that IL-1α may play in development of chronic pain as well as the interplay it has with IL-1β.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2023

Author dc:creator

• Messer, Taylor B.

Advisor dc:contributor.advisor

• Baumbauer, Kyle

• Neurosciences
• Chronic Pain
• IL-1R1
• IL-1α
• IL-1β
• Spinal Cord Injury

Statement dc:rights

• Copyright held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:19075

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/36407