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Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund's adjuvant model of orofacial pain.

ABSTRACT: BACKGROUND:The neurochemical background of the evolution of headache disorders, still remains partially undiscovered. Accordingly, our aim was to further explore the neurochemical profile of Complete Freund's adjuvant (CFA)-induced orofacial pain, involving finding the shift point regarding small molecule neurotransmitter concentrations changes vs. that of the previously characterized headache-related neuropeptides. The investigated neurotransmitters consisted of glutamate, ?-aminobutyric acid, noradrenalin and serotonin. Furthermore, in light of its influence on glutamatergic neurotransmission, we measured the level of kynurenic acid (KYNA) and its precursors in the kynurenine (KYN) pathway (KP) of tryptophan metabolism. METHODS:The effect of CFA was evaluated in male Sprague Dawley rats. Animals were injected with CFA (1?mg/ml, 50??l/animal) into the right whisker pad. We applied high-performance liquid chromatography to determine the concentrations of the above-mentioned compounds from the trigeminal nucleus caudalis (TNC) and somatosensory cortex (ssCX) of rats. Furthermore, we measured some of these metabolites from the cerebrospinal fluid and plasma as well. Afterwards, we carried out permutation t-tests as post hoc analysis for pairwise comparison. RESULTS:Our results demonstrated that 24?h after CFA treatment, the level of glutamate, KYNA and that of its precursor, KYN was still elevated in the TNC, all diminishing by 48?h. In the ssCX, significant concentration increases of KYNA and serotonin were found. CONCLUSION:This is the first study assessing neurotransmitter changes in the TNC and ssCX following CFA treatment, confirming the dominant role of glutamate in early pain processing and a compensatory elevation of KYNA with anti-glutamatergic properties. Furthermore, the current findings draw attention to the limited time interval where medications can target the glutamatergic pathways.

SUBMITTER: Cseh EK

PROVIDER: S-EPMC7175490 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund's adjuvant model of orofacial pain.

Cseh Edina K EK Veres Gábor G Körtési Tamás T Polyák Helga H Nánási Nikolett N Tajti János J Párdutz Árpád Á Klivényi Péter P Vécsei László L Zádori Dénes D

The journal of headache and pain 20200421 1

<h4>Background</h4>The neurochemical background of the evolution of headache disorders, still remains partially undiscovered. Accordingly, our aim was to further explore the neurochemical profile of Complete Freund's adjuvant (CFA)-induced orofacial pain, involving finding the shift point regarding small molecule neurotransmitter concentrations changes vs. that of the previously characterized headache-related neuropeptides. The investigated neurotransmitters consisted of glutamate, γ-aminobutyri ...[more]

PMID: 32316909

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Project description: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 gene-related 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??l 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.

Dataset Information

Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund's adjuvant model of orofacial pain.

Publications

Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund's adjuvant model of orofacial pain.

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