Abstract
BackgroundThe 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-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.MethodsThe effect of CFA was evaluated in male Sprague Dawley rats. Animals were injected with CFA (1 mg/ml, 50 μl/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.ResultsOur 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.ConclusionThis 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.
Highlights
The neurochemical background of the evolution of headache disorders, still remains partially undiscovered
Similar to the previous experiment on pituitary adenylate cyclase-activating peptide (PACAP) and calcitonin gene-related peptide (CGRP) in the same model [9], only sham-injected rats processed 24 h following the injection were used as CO, as a pilot study conducted on naïve and shaminjected rats demonstrated that there is no difference in the level of the metabolites of interest, in neither trigeminal nucleus caudalis (TNC), nor somatosensory cortex (ssCX) (n = 3 in each group, data not shown)
Concentration levels of the assessed compounds in the TNC and ssCX First of all, both contralateral and ipsilateral central nervous system (CNS) regions were measured separately, but we did not find significant differences in concentrations of any of the metabolites between the two sides, so the coherent data were pooled for further analysis
Summary
The neurochemical background of the evolution of headache disorders, still remains partially undiscovered. 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 pathomechanism of orofacial pain and headache disorders, is not fully understood [1], the activation and sensitization of the trigeminovascular system (TS) probably takes part in the evolution of symptoms [2,3,4] The pathomechanism of these disorders may be further investigated by using animal models with the activation of nociceptive pathways of the TS [1, 3, 5]. There are no studies which aimed at the investigation of the small molecule neurotransmitters and neuromodulators and some of their precursors (glutamate (Glu), γaminobutyric acid (GABA), setotonin (5-hydroxy-tryptamine; 5-HT), noradrenaline (NA), tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA)) in this model with established or presumed role in the development of peripheral and central sensitization during headache. Finding the transition point where the dominance of small molecule mediated neurotransmission shifts to that of the PACAP and CGRP mentioned earlier may have significant therapeutic consequences in view of the different targeted approaches
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