Mild Traumatic Brain Injury Causes Nociceptive Sensitization through Spinal Chemokine Upregulation

AbstractHigh 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.

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Moderate–severe traumatic brain injury causes delayed loss of white matter integrity: Evidence of fornix deterioration in the chronic stage of injury

Brain Injury ◽

10.3109/02699052.2013.823659 ◽

2013 ◽

Vol 27 (12) ◽

pp. 1415-1422 ◽

Cited By ~ 28

Author(s):

Areeba Adnan ◽

Adrian Crawley ◽

David Mikulis ◽

Morris Moscovitch ◽

Brenda Colella ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Severe Traumatic Brain Injury ◽

White Matter Integrity ◽

Chronic Stage ◽

Injury Causes

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Structural brain connectivity predicts acute pain after mild traumatic brain injury

10.1101/2021.11.12.468345 ◽

2021 ◽

Author(s):

Paulo Branco ◽

Noam Bosak ◽

Jannis Bielefeld ◽

Olivia Cong ◽

Yelena Granovsky ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Mild Traumatic Brain Injury ◽

Acute Pain ◽

Pain Perception ◽

Strong Predictor ◽

Pain Modulation ◽

Acute Injury ◽

Post Injury

Mild traumatic brain injury, mTBI, is a leading cause of disability worldwide, with acute pain manifesting as one of its most debilitating symptoms. Understanding acute post-injury pain is important since it is a strong predictor of long-term outcomes. In this study, we imaged the brains of 172 patients with mTBI, following a motorized vehicle collision and used a machine learning approach to extract white matter structural and resting state fMRI functional connectivity measures to predict acute pain. Stronger white matter tracts within the sensorimotor, thalamic-cortical, and default-mode systems predicted 20% of the variance in pain severity within 72 hours of the injury. This result generalized in two independent groups: 39 mTBI patients and 13 mTBI patients without whiplash symptoms. White matter measures collected at 6-months after the collision still predicted mTBI pain at that timepoint (n = 36). These white-matter connections were associated with two nociceptive psychophysical outcomes tested at a remote body site – namely conditioned pain modulation and magnitude of suprathreshold pain–, and with pain sensitivity questionnaire scores. Our validated findings demonstrate a stable white-matter network, the properties of which determine a significant amount of pain experienced after acute injury, pinpointing a circuitry engaged in the transformation and amplification of nociceptive inputs to pain perception.

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Reducing head computed tomography after mild traumatic brain injury: Screening value of clinical findings and S100B protein levels

Brain Injury ◽

10.3109/02699052.2015.1091504 ◽

2015 ◽

Vol 30 (2) ◽

pp. 172-178 ◽

Cited By ~ 5

Author(s):

Shadi Asadollahi ◽

Kamran Heidari ◽

Mehrdad Taghizadeh ◽

Arash Mohammad Seidabadi ◽

Morteza Jamshidian ◽

...

Keyword(s):

Computed Tomography ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Clinical Findings ◽

S100b Protein ◽

Protein Levels ◽

Injury Screening ◽

Head Computed Tomography

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Somatosensory dysfunction in patients with posttraumatic headache: A systematic review

Cephalalgia ◽

10.1177/03331024211030496 ◽

2021 ◽

pp. 033310242110304

Author(s):

Julia Jessen ◽

Özüm S. Özgül ◽

Oliver Höffken ◽

Peter Schwenkreis ◽

Martin Tegenthoff ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Pain Perception ◽

Treatment Options ◽

Pain Modulation ◽

Sensory Function ◽

Posttraumatic Headache ◽

Pubmed Database ◽

Underlying Mechanisms ◽

Sensory Profiles

Objectives Aim of the review is to summarize the knowledge about the sensory function and pain modulatory systems in posttraumatic headache and discuss its possible role in patients with posttraumatic headache. Background Posttraumatic headache is the most common complication after traumatic brain injury, and significantly impacts patients’ quality of life. Even though it has a high prevalence, its origin and pathophysiology are poorly understood. Thereby, the existing treatment options are insufficient. Identifying its mechanisms can be an important step forward to develop target-based personalized treatment. Methods We searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with headache after brain injury. Results The studies showed heterogenous alterations in sensory profiles (especially in heat and pressure pain perception) compared to healthy controls and headache-free traumatic brain injury-patients. Furthermore, pain inhibition capacity was found to be diminished in subjects with posttraumatic headache. Conclusions Due to the small number of heterogenous studies a distinct sensory pattern for patients with posttraumatic headache could not be identified. Further research is needed to clarify the underlying mechanisms and biomarkers for prediction of development and persistence of posttraumatic headache.

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An Exploratory Study of Endogenous Pain Modulatory Function in Patients Following Mild Traumatic Brain Injury

Pain Medicine ◽

10.1093/pm/pnz058 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2198-2207 ◽

Cited By ~ 2

Author(s):

Christopher Carey ◽

Jonathan Saxe ◽

Fletcher A White ◽

Kelly M Naugle

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Exploratory Study ◽

Pain Modulation ◽

Conditioned Pain Modulation ◽

Pain Thresholds ◽

Pressure Pain Thresholds ◽

Post Traumatic ◽

Headache Pain ◽

Pain Inhibition

AbstractBackground. Recent animal research suggests that mild traumatic brain injury (mTBI) facilitates abnormal endogenous modulation of pain, potentially underlying the increased risk for persistent headaches following injury. However, no human studies have directly assessed the functioning of endogenous facilitory and inhibitory systems in the early stages after an mTBI. Objective. The purpose of this exploratory study was to examine trigeminal sensitization and endogenous pain inhibitory capacity in mTBI patients in the acute stage of injury compared with matched controls. We also examined whether post-traumatic headache pain intensity within the mTBI sample was related to sensitization and pain inhibitory capacity. Methods. Twenty-four mTBI patients recruited from emergency departments and 21 age-, race-, and sex-matched controls completed one experimental session. During this session, participants completed quantitative sensory tests measuring trigeminal sensitization (pressure pain thresholds and temporal summation of pain in the head) and endogenous pain inhibition (conditioned pain modulation). Participants also completed validated questionnaires measuring headache pain, depression, anxiety, and pain catastrophizing. Results. The results revealed that the mTBI group exhibited significantly decreased pressure pain thresholds of the head and decreased pain inhibition on the conditioned pain modulation test compared with the control group. Furthermore, correlational analysis showed that the measures of trigeminal sensitization and depression were significantly associated with headache pain intensity within the mTBI group. Conclusions. In conclusion, mTBI patients may be at risk for maladaptive changes to the functioning of endogenous pain modulatory systems following head injury that could increase risk for post-traumatic headaches.

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Repeated mild traumatic brain injury causes persistent changes in histone deacetylase function in hippocampus: Implications in learning and memory deficits in rats

Brain Research ◽

10.1016/j.brainres.2019.01.022 ◽

2019 ◽

Vol 1711 ◽

pp. 183-192 ◽

Cited By ~ 5

Author(s):

Sneha Sagarkar ◽

Nagalakshmi Balasubramanian ◽

Shruti Mishra ◽

Amit G. Choudhary ◽

Dadasaheb M. Kokare ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Learning And Memory ◽

Histone Deacetylase ◽

Mild Traumatic Brain Injury ◽

Memory Deficits ◽

Learning And Memory Deficits ◽

Injury Causes

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Injury Causes and Severity in Pediatric Traumatic Brain Injury Patients Admitted to the Ward or Intensive Care Unit: A Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study

Frontiers in Neurology ◽

10.3389/fneur.2020.00345 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lennart Riemann ◽

Klaus Zweckberger ◽

Andreas Unterberg ◽

Ahmed El Damaty ◽

Alexander Younsi ◽

...

Keyword(s):

Intensive Care Unit ◽

Traumatic Brain Injury ◽

Intensive Care ◽

Brain Injury ◽

Effectiveness Research ◽

Pediatric Traumatic Brain Injury ◽

Injury Causes

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Traumatic brain injury in mice induces changes in the expression of the XCL1/XCR1 and XCL1/ITGA9 axes

Pharmacological Reports ◽

10.1007/s43440-020-00187-y ◽

2020 ◽

Vol 72 (6) ◽

pp. 1579-1592

Author(s):

Agata Ciechanowska ◽

Katarzyna Popiolek-Barczyk ◽

Katarzyna Ciapała ◽

Katarzyna Pawlik ◽

Marco Oggioni ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Therapeutic Potential ◽

Brain Structures ◽

Pharmacological Intervention ◽

Brain Areas ◽

Cellular Origin ◽

Protein Levels ◽

Chemokine Ligand

Abstract Background Every year, millions of people suffer from various forms of traumatic brain injury (TBI), and new approaches with therapeutic potential are required. Although chemokines are known to be involved in brain injury, the importance of X-C motif chemokine ligand 1 (XCL1) and its receptors, X-C motif chemokine receptor 1 (XCR1) and alpha-9 integrin (ITGA9), in the progression of TBI remain unknown. Methods Using RT-qPCR/Western blot/ELISA techniques, changes in the mRNA/protein levels of XCL1 and its two receptors, in brain areas at different time points were measured in a mouse model of TBI. Moreover, their cellular origin and possible changes in expression were evaluated in primary glial cell cultures. Results Studies revealed the spatiotemporal upregulation of the mRNA expression of XCL1, XCR1 and ITGA9 in all the examined brain areas (cortex, thalamus, and hippocampus) and at most of the evaluated stages after brain injury (24 h; 4, 7 days; 2, 5 weeks), except for ITGA9 in the thalamus. Moreover, changes in XCL1 protein levels occurred in all the studied brain structures; the strongest upregulation was observed 24 h after trauma. Our in vitro experiments proved that primary murine microglial and astroglial cells expressed XCR1 and ITGA9, however they seemed not to be a main source of XCL1. Conclusions These findings indicate that the XCL1/XCR1 and XCL1/ITGA9 axes may participate in the development of TBI. The XCL1 can be considered as one of the triggers of secondary injury, therefore XCR1 and ITGA9 may be important targets for pharmacological intervention after traumatic brain injury. Graphic abstract

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The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study

The Journal of Headache and Pain ◽

10.1186/s10194-020-01207-1 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Kelly M. Naugle ◽

Christopher Carey ◽

Eric Evans ◽

Jonathan Saxe ◽

Ryan Overman ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Pain Catastrophizing ◽

Pain Modulation ◽

Conditioned Pain Modulation ◽

Mild Tbi ◽

Inhibitory Capacity ◽

Pressure Pain Thresholds ◽

Post Traumatic

Abstract Background Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients. Methods Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1–2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies – Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data. Results The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1–2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1–2 weeks predicted persistent PTH classification at 4 months post injury. Conclusions Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH.

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