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

M. Lukács,K. Warfvinge,J. Tajti,L. Vécsei,J. Toldi,F. Fülöp,L. Edvinsson

doi:10.1186/s10194-017-0746-x

Abstract

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.

Highlights

Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role
We found activation of satellite glial cells and neurons of the trigeminal ganglion (IL-1, pERK1/2) that were abolished by the kynurenic acid (KYNA)-analogue, SZR72 [17] possibly acting on peripheral and central gluatamate receptors (30)
Complete Freund’s Adjuvant (CFA) is a potent immun- potentiator, used in various peripheral pain model. (Spinal distribution of c-Fos activated neurons expressing enkephalin in acute and chronic pain models, 1st manu) We asked the question whether application of CFA on a defined area of the dura mater could cause activation of second-order neurons in the trigeminal nucleus caudalis (TNC) and whether this activation can be mitigated by systemic adminstration of a KYNA analogue

Summary

Introduction

Migraine 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). Previous studies have shown that application of inflammatory substances on the dura mater causes central sensitisation of the neurons in TNC and at C1-C2 levels of the spinal cord [6, 10, 11]. We found activation of satellite glial cells and neurons of the trigeminal ganglion (IL-1, pERK1/2) that were abolished by the KYNA-analogue, SZR72 [17] possibly acting on peripheral and central gluatamate receptors (30). The present study was designed to examine whether dural application of CFA can cause activation of the central part of the trigeminalvascular system,: the TNC and C1-C2 regions of the spinal cord. We asked the question whether the CFA-induced activation might be mitigated by use of SZR72 intraperitoneally

Methods

Results

Discussion

Conclusion