Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion

Csáti, Anett; Edvinsson, Lars; Vécsei, László; Toldi, József; Fülöp, Ferenc; Tajti, János; Warfvinge, Karin

doi:10.1186/s10194-015-0581-x

Cited by 48 publications

(45 citation statements)

References 64 publications

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“…NMDA receptors are critical for the induction of spinal LTP (Liu and Sandk€ uhler, 1995). In the present work, we demonstrated that blocking NMDA receptors with D-AP5 suppressed HFSinduced CGRP increases ( Figures 2G and 2H), which is consistent with previous studies (Csá ti et al, 2015;Wong et al, 2014). Because synaptic functional plasticity leads to structural plasticity, the effect of the NMDA receptor antagonist D-AP5 on CGRP terminals may result from inhibition of spinal LTP.…”

Section: Action Potential Discharge In Nociceptive Afferentssupporting

confidence: 91%

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

et al. 2019

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Graphical AbstractHighlights d HFS triggers synaptic plasticity of CGRP afferents and chronic pain d LTP-inducible HFS activates spinal microglia through CSF1 signaling d Microglial BDNF is essential for HFS-induced spinal LTP and chronic pain SUMMARY Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.

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Section: Action Potential Discharge In Nociceptive Afferentssupporting

confidence: 91%

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

et al. 2019

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“…Previous work has shown a positive effect in TG following CFA injection into the temporomandibular joint [31] while SZR 72 decreased c-fos activation in the TNC in nitroglycerin induced trigeminal activation [32]. We have reported that one dose of SZR 72 is able to reduce dura mater applied CFA induced activation in the TG [16].…”

Section: Discussionmentioning

confidence: 83%

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

et al. 2017

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BackgroundMigraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund’s Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.MethodsActivation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C1-C2 regions of the spinal cord.ResultsWe found that CFA increased c-fos and glutamate immunoreactivity in TNC and C1-C2 neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.ConclusionThis is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.

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“…In our previous study, we investigated the effect of CFA on the expression of mitogen-activated protein kinases (MAPK), which play essential roles in pain processing. Administration of CFA in the TMJ caused significant extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPK increase in the TRG [42]. Dural administration of CFA resulted elevated ERK1/2, interleukin-1β and CGRP expression in the TRG [11], as well as increased c-fos and glutamate immunoreactivity in the TNC and cervical neurons [43].…”

Section: Role Of Neuropeptides In Preclinical Migraine Modelsmentioning

confidence: 99%

The effect of orofacial complete Freund’s adjuvant treatment on the expression of migraine-related molecules

et al. 2019

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Background: Migraine is a neurovascular primary headache disorder, which causes significant socioeconomic problems worldwide. The pathomechanism of disease is enigmatic, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Migraine research of recent years has focused on neuropeptides, such as calcitonin generelated peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide 1-38 (PACAP1-38) as potential pathogenic factors and possible therapeutic offensives. The goal of present study was to investigate the simultaneous expression of CGRP and precursor of PACAP1-38 (preproPACAP) in the central region of the TS in a time-dependent manner following TS activation in rats. Methods: The right whisker pad of rats was injected with 50 μl Complete Freund's Adjuvant (CFA) or saline. A mechanical allodynia test was performed with von Frey filaments before and after treatment. Transcardial perfusion of the animals was initiated 24, 48, 72 and 120 h after injection, followed by the dissection of the nucleus trigeminus caudalis (TNC). After preparation, the samples were stored at − 80°C until further use. The relative optical density of CGRP and preproPACAP was analyzed by Western blot. One-way ANOVA and Kruskal-Wallis followed by Tukey post hoc test were used to evaluate the data. Regression analysis was applied to explore the correlation between neuropeptides expression and hyperalgesia. Results: Orofacial CFA injection resulted in significant CGRP and preproPACAP release in the TNC 24, 48, 72 and 120 h after the treatment. The level of neuropeptides reached its maximum at 72 h after CFA injection, corresponding to the peak of facial allodynia. Negative, linear correlation was detected between the expression level of neuropeptides and value of mechanonociceptive threshold. Conclusion: This is the first study which suggests that the expression of CGRP and preproPACAP simultaneously increases in the central region of activated TS and it influences the formation of mechanical hyperalgesia. Our results contribute to a better understanding of migraine pathogenesis and thereby to the development of more effective therapeutic approaches.

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Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion

Cited by 48 publications

References 64 publications

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

The effect of orofacial complete Freund’s adjuvant treatment on the expression of migraine-related molecules

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