Intact mast cell content during mild head injury is required for the development of latent pain sensitization - implications for mechanisms underlying post-traumatic headache

Bree, Dara; Levy, Dan

doi:10.1101/392928

Cited by 6 publications

(17 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, to produce a more severe CHI we increased the gravity force by employing a heavier mass (450 g weight), and maintained the same height as in our previous CHI paradigm. The finding that the 450 g CHI paradigm was associated with a ~20% mortality rate, while our earlier studies indicated no mortality using the milder 250 g CHI paradigm (9,22) points to increased injury severity, and is in agreement with previous studies that investigated the effects of a graded mechanical impact levels (27). Our open-field testing data indicated no change in total distance traveled suggesting no impairment in gross motor activity, similar to the effect of a 250 g weight drop injury.…”

Section: Discussionsupporting

confidence: 90%

“…This dosing regimen has been shown previously to alleviate PTH-like pain behaviors (i.e. cephalic allodynia) following mild CHI in male rats (9,22), and male mice (11), as well as pain behaviors in other chronic migraine models (24).…”

Section: Pharmacological Treatmentsmentioning

confidence: 96%

“…Development of hind paw tactile hypersensitivity was tested by stimulating the mid-dorsal part of the hind paw using the VF filaments. We evaluated changes in withdrawal thresholds, as well as non-reflexive pain responses to the stimulation using a method previously described in this and other headache models (20)(21)(22) by recording 4 behavioral responses adapted from Vos et al (23) as follows: 0) No response: rat did not display any response to stimulation 1) Detection: rat turned its head towards stimulating object and latter is explored usually by sniffing; 2) Withdrawal: rat turned its head away or pulled it briskly away from stimulating object (usually followed by scratching or grooming of stimulated region); 3) Escape/Attack: rat turned its body briskly in the holding apparatus in order to escape stimulation or attacked (biting and grabbing movements) the stimulating object. Starting with the lowest force, each filament was applied 3 times with an intraapplication interval of 5 seconds and the behavior that was observed at least twice was recorded.…”

Section: Assessment Of Tactile Pain Hypersensitivitymentioning

confidence: 99%

“…In our previous studies, we examined changes in pain behaviors resembling PTH in response to a mild, concussive CHI involving a single 250 g weight drop in rats (9,22). In this CHI paradigm, male rats displayed acute changes in open field behavior, as well as mechanical pain hypersensitivity, limited to the cephalic region, that recovered at day 14 post CHI.…”

Section: Open Field Behaviormentioning

confidence: 99%

See 3 more Smart Citations

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Bree

Stratton²,

Levy

2020

Preprint

Self Cite

View full text Add to dashboard Cite

Introduction: Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying PTH. To address these shortcomings, we previously characterized the development of PTH-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further develop this preclinical model by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral CGRP signaling by testing the effect of systemic anti-CGRP monoclonal antibody (anti-CGRP mAb).Methods: Adult male Sprague Dawley rats (total n=138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: a single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of headache-related cephalic and extracephalic mechanical pain hypersensitivity were assessed up to 42 days post head trauma. Treatment included systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody (30 mg/kg.).Results: Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic and extracephalic mechanical pain hypersensitivity that resolved by 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as prolonged cephalic and extracephalic mechanical pain hypersensitivity. Early and prolonged anti-CGRP mAb treatment inhibited the development of the cephalic, but not extracephalic pain hypersensitivities in both the severe and repetitive subconcussive head impact models. Conclusions:When compared to the data obtained from male rats in the previous study, a more severe head injury gives rise to a prolonged state of cephalic and extracephalic hyperalgesia. Such enhanced headache-like behaviors also occur following repetitive, subconcussive head impacts.Extended headache-like behaviors following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-CGRP mAb treatment, suggesting a mechanism linked to peripheral CGRP signaling.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Pharmacological Treatmentsmentioning

confidence: 96%

Section: Assessment Of Tactile Pain Hypersensitivitymentioning

confidence: 99%

Section: Open Field Behaviormentioning

confidence: 99%

See 2 more Smart Citations

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Bree

Stratton²,

Levy

2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, in PTH it is plausible to hypothesize that direct trauma to the head may be enough to initiate acute periosteal and persistent dural mast cell degranulation for at least 30 days following a trauma, resulting in the development of headache [ 40 , 47 ]. On the other side, Bree and Levy found that persistent activation of meningeal mast cells after mCHI is not required for the development of cephalic hypersensitivity, so that authors hypothesized that CGRP mediates the PTH-related pain behavior through a mechanism independent of ongoing meningeal mast cells pro-inflammatory response [ 68 ].…”

Section: Main Textmentioning

confidence: 99%

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence

et al. 2020

View full text Add to dashboard Cite

Background: According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months. Main body: Currently, due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH. Despite representing a simplification of a complex disorder and displaying different limitations concerning the human condition, animal models are still a mainstay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies. Different models reproduce different types of trauma and have been ideated in order to ensure maximal proximity to the human condition and optimal experimental reproducibility. Conclusion: At present, despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified. Although facing limitations, animal models are needed to improve understanding of PTH. The knowledge of currently available models is necessary to all researchers who want to investigate PTH and contribute to unravel its mechanisms.

show abstract

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Kempuraj

Ahmed

Selvakumar

et al. 2020

Mediators of Inflammation

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.

show abstract

Intact mast cell content during mild head injury is required for the development of latent pain sensitization - implications for mechanisms underlying post-traumatic headache

Cited by 6 publications

References 54 publications

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Contact Info

Product

Resources

About