Browsing by Subject "C3aR1"

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    Complement-3a receptor involvement in peripheral and central neuropathic pain
    (2019-09) Cook, Jennifer
    VGF (non-acronymic), a neuropeptide precursor protein related to the chromogranin family, has been implicated in neuroplasticity associated with depression, learning and memory, and chronic pain. The Vulchanova lab has previously demonstrated that the VGF-derived peptide TLQP-21 contributes to both the development and maintenance of hypersensitivity after peripheral nerve injury and inflammation. The receptor for TLQP-21 is the complement-3a receptor C3aR1. Although the complement system has been implicated in mechanisms of neuropathic pain, the potential relevance of C3aR1 in these processes has not been addressed. This thesis examines the involvement of C3aR1 signaling following spared nerve injury (SNI) and spinal cord injury (SCI). I hypothesized that C3aR1 located on microglia are a key signaling mediator in neuropathic pain following peripheral and central injury. In this thesis, I show that C3aR1 is localized to microglia in both naïve mice, and mice following SNI and SCI. Following SNI, an antagonist to C3aR1 was able to transiently attenuate mechanical hypersensitivity. Additionally, I found that TLQP-21 specifically activates C3aR1 located on microglia. I identified that there was upregulation of C3aR1 in a time-dependent manner following SNI and SCI. The early increase of receptor expression indicates a potentially important role of C3aR1 signaling throughout the acute stages of peripheral and central nervous system injury. Prior to this thesis work, there were limited studies examining sensory changes occurring in male mice following SCI. I provide the most thorough characterization of behavior following SCI in male mice to date, and show for the first time that SCI mice exhibit a dramatic loss of light touch sensitivity. Utilizing an antisense oligonucleotide, I show a potentially protective effect of knocking down the C3aR1 receptor during the acute phase of spinal cord injury. I found that knockdown attenuated the loss of light touch sensitivity seen in spinal cord injury animals. Overall, this thesis highlights the potential relevance of C3aR1 as a therapeutic target following injury, and uncovers the complex role complement receptor-mediated immune signaling has in neuropathic pain.