Abstract
High rates of acute and chronic pain are associated with traumatic brain injury (TBI), but mechanisms responsible for the association remain elusive. Recent data suggest dysregulated descending pain modulation circuitry could be involved. Based on these and other observations, we hypothesized that serotonin (5-HT)-dependent activation of spinal CXC Motif Chemokine Receptor 2 (CXCR2) may support TBI-related nociceptive sensitization in a mouse model of mild TBI (mTBI). We observed that systemic 5-HT depletion with p-chlorophenylalanine attenuated mechanical hypersensitivity seen after mTBI. Likewise, selective spinal 5-HT fiber depletion with 5,7-dihydroxytryptamine (5,7-DHT) reduced hypersensitivity after mTBI. Consistent with a role for spinal 5-HT3 serotonin receptors, intrathecal ondansetron administration after TBI dose-dependently attenuated nociceptive sensitization. Also, selective CXCR2 antagonist SCH527123 treatment attenuated mechanical hypersensitivity after mTBI. Furthermore, spinal CXCL1 and CXCL2 mRNA and protein levels were increased after mTBI as were GFAP and IBA-1 markers. Spinal 5,7-DHT application reduced both chemokine expression and glial activation. Our results suggest dual pathways for nociceptive sensitization after mTBI, direct 5-HT effect through 5-HT3 receptors and indirectly through upregulation of chemokine signaling. Designing novel clinical interventions against either the 5-HT3 mediated component or chemokine pathway may be beneficial in treating pain frequently seen in patients after mTBI.
Highlights
Traumatic brain injury (TBI) has an annual incidence of 295 per 100,000 of the population and is a leading cause of trauma-related disability worldwide[1,2]
We have previously shown an increase in hindpaw mechanical sensitivity after mild TBI (mTBI) in mice with peak increases lasting for 72 h and a gradual recovery to baseline values by 14 days post-injury[13]
To assess the role of serotonin signaling in mTBI-induced mechanical hypersensitivity, systemic 5-hydroxytryptamine (5-HT) depletion was achieved with once daily treatment with p-Chlorophenylalanine (PCPA) for four days
Summary
Traumatic brain injury (TBI) has an annual incidence of 295 per 100,000 of the population and is a leading cause of trauma-related disability worldwide[1,2]. Further studies demonstrated a strong association between the spinal dysregulated serotonin input, neuroinflammation and neuronal activation early on after LFP injury[17] At this time, interactions between TBI-induced dysregulation of endogenous pain control circuits, neuroinflammation and CXCR2-dependent nociceptive sensitization after mTBI have not been identified. We hypothesized that activated descending serotonergic facilitation would be responsible for the enhanced spinal neuroinflammation, upregulated chemokine expression and nociceptive sensitization seen after TBI. This type of mechanism, if demonstrated to exist, might explain the pain and nociceptive hypersensitivity common in patients after TBI, and would offer avenues towards novel clinical treatments of this important TBI-related pain problem
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
