A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine

Wu, Shouyi; Ren, Xiao; Zhu, Chenlu; Wang, Wei; Zhang, Kaibo; Li, Zhilei; Liu, Xuejiao; Wang, Yonggang

doi:10.1186/s10194-022-01496-8

Cited by 25 publications

(16 citation statements)

References 53 publications

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“…Of note, in contrast to frequent reports implicating ventral posterolateral (VPL) nucleus and ventral posteromedial (VPM) nucleus of the thalamus in migraine (70,71) and pain processing (13,15) we observed no increase in c-fos expression in either the VPL or VPM. Consistent with our results in this PTH model, previous c-fos based neural activity mapping in migraine models (72,73) similarly reported c-fos increases in SpVc and SSp. However, neither study reported changes in the NAc and therefore this may represent a unique area activated by mTBI induced PTH.…”

Section: Discussionsupporting

confidence: 93%

Identification of brain areas in mice with peak neural activity across the acute and persistent phases of post-traumatic headache

Rudolph,

Kopruszinski,

et al. 2023

Cephalalgia

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Background Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache. Methods Male and female C57BL/6 J mice were briefly anesthetized and subjected to a sham procedure or a weight drop closed-head mild traumatic brain injury . Cutaneous allodynia was assessed in the periorbital and hindpaw regions using von Frey filaments. Immunohistochemical c-fos based neural activity mapping was then performed on sections from whole brain across the development of post-traumatic headache (i.e. peak of the acute phase at 2 days post- mild traumatic brain injury), start of the persistent phase (i.e. >14 days post-mild traumatic brain injury) or after provocation with stress (bright light). Brain areas with consistent and peak levels of c-fos expression across mild traumatic brain injury induced post-traumatic headache were identified and included for further analysis. Results Following mild traumatic brain injury, periorbital and hindpaw allodynia was observed in both male and female mice. This allodynia was transient and subsided within the first 14 days post-mild traumatic brain injury and is representative of acute post-traumatic headache. After this acute post-traumatic headache phase, exposure of mild traumatic brain injury mice to a bright light stress reinstated periorbital and hindpaw allodynia for several hours – indicative of the development of persistent post-traumatic headache. Acute post-traumatic headache was coincident with an increase in neuronal c-fos labeling in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and the nucleus accumbens. Neuronal activation returned to baseline levels by the persistent post-traumatic headache phase in the spinal nucleus of the trigeminal caudalis and primary somatosensory cortex but remained elevated in the nucleus accumbens. In the persistent post-traumatic headache phase, coincident with allodynia observed following bright light stress, we observed bright light stress-induced c-fos neural activation in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens. Conclusion Examination of mild traumatic brain injury-induced changes in peak c-fos expression revealed brain regions with significantly increased neural activity across the acute and persistent phases of post-traumatic headache. Our findings suggest mild traumatic brain injury-induced post-traumatic headache produces neural activation along pain relevant pathways at time-points matching post-traumatic headache-like pain behaviors. These observations suggest that the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens may contribute to both the induction and maintenance of post-traumatic headache.

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Section: Discussionsupporting

confidence: 93%

Identification of brain areas in mice with peak neural activity across the acute and persistent phases of post-traumatic headache

Rudolph,

Kopruszinski,

et al. 2023

Cephalalgia

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“…Previous studies with LEV-induced chronic migraine model adopted the 2nd hour as the testing time for LEV post-treatment responses. This may be the reason why lower thresholds were not consistently observed during the establishment of chronic migraine model in these studies (38,50,51). We observed a similar degree of threshold reduction in both LEV and NTG groups, however in the LEV group, decay time of threshold was signi cantly shorter in comparison to NTG group.…”

Section: Discussionmentioning

confidence: 60%

Levcromakalim Provokes a Rapid-Onset Migraine-like Phenotype Without Inducing Cortical Spreading Depolarization

Alpay

Akaydin

Cimen

et al. 2023

Preprint

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Background Migraine headache attacks and accompanying sensory augmentation can be induced by several agents including levcromakalim (LEV), that is also capable of provoking aura-like symptoms in migraineurs. We investigated whether acute LEV injection causes migraine-like phenotype in rats and induces/modulates cortical spreading depolarization (CSD), a rodent model of migraine aura. Methods Wistar rats were administered LEV (1mg/kg, i.p.) and compared to control (CTRL, vehicle, i.p.) and nitroglycerin (NTG, 10 mg/kg, i.p.) groups. Von Frey filaments were used to examine the periorbital and hindpaw mechanical allodynia. Dark-light box (DLB), elevated plus maze (EPM), and open field arena (OFA) were used to evaluate light sensitivity and anxiety-related behaviors. The effects of LEV on CSD parameters, somatosensory evoked potentials, and baseline dural EEG were investigated Possible CSD-induced c-fos expression was studied with Western Blot. BBB integrity in cortex is examined with Evans Blue Assay. Results LEV and NTG administration robustly reduced periorbital mechanical thresholds in rats and induced anxiety-like behaviors and photophobia within 30 and 120 minutes, respectively. LEV induced migraine like phenotype recovered in 2 hours while NTG group were not fully recovered before 4 hours. Both LEV and NTG did not provoke DC shift, EEG alterations or cortical c-fos expression characteristic to CSD. LEV did not affect KCl-induced CSD parameters except for an increase in propagation failure. However, NTG significantly increased both CSD susceptibility and propagation failure. Somatosensory evoked potential configurations were not altered in both LEV and NTG groups, but SSEP latencies were prolonged after CSD. Acute LEV or NTG injection did not increase cortical BBB permeability. Conclusions Acute systemic LEV administration induced the fastest manifestation and recovery of migraine like phenotype which was not mediated by CSD waves in the cerebral cortex. CSD modulating effects of LEV were less prominent compared to NTG, an agent without aura provoking properties. We suppose LEV triggered rapid-onset migraine-like symptoms are probably related to functional alterations in the trigeminal nociceptive system and K + channel opening properties of LEV. Understanding the neurobiological mechanisms of this nociceptive window, may provide a novel targets in migraine treatment.

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“…1 C-E). C-Fos is thought to be a biomarker of neuronal activation responding to nociceptive stimuli, which is highly correlated with migraine pathogenesis [ 43 ]. Our results indicated that the protein expression of c-Fos in the TNC was upregulated significantly in the NTG group when compared with the saline group ( p < 0.001; Fig.…”

Section: Resultsmentioning

confidence: 99%

PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

et al. 2023

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Aims Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. Methods Sprague–Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. Results The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. Conclusions Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.

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A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine

Cited by 25 publications

References 53 publications

Identification of brain areas in mice with peak neural activity across the acute and persistent phases of post-traumatic headache

Identification of brain areas in mice with peak neural activity across the acute and persistent phases of post-traumatic headache

Levcromakalim Provokes a Rapid-Onset Migraine-like Phenotype Without Inducing Cortical Spreading Depolarization

PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

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