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, 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. Methods: The 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.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.

Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

“…Glutamate excess can exacerbate pain, while KYNA is able to inhibit glutamate excitotoxicity via NMDA receptor antagonism. Altered glutamate metabolism in migraine is undisputable and KYNA can be protective against trigeminal hyperactivity, but medications targeting the glutamatergic pathway have limited time interval [ 26 ].…”

“…α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, G protein coupled receptor 35, aryl hydrocarbon receptors, α7-nicotinic acetylcholine receptor), enabling widespread modulating properties [ 22 ]. Downregulated KP was observed in different animal models of TS activation [ 23 – 26 ], while administration of KYN, KYNA and certain KYNA-derivatives seemed effective in preventing migraine-related neuronal, molecular and electrophysiological alterations in preclinical studies [ 5 , 27 – 30 ].…”

The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents

“…Upstream of the kynurenine metabolic pathway, TRP metabolizes into serotonin, a NT implicated both in the pathogenesis [ 106 , 107 ] as well as therapy [ 108 ] in migraineurs. Cseh et al measured elevated levels of not only glutamate, but also of KYN and KYNA in TNC following a CFA whisker pad injection [ 109 ]. Within the somatosensory cortex, significant increases in 5-HT and KYNA concentrations were found.…”

“…KYN, KYNA, as well as 5-HT may represent a feedback mechanism to diminish glutamate sensitization and trigeminovascular pathway activation, respectively [ 110 ]. Of note, the observed metabolite concentration changes occurred in a narrow time interval between 24 and 48 h, which corresponds to central and peripheral sensitization of the trigeminovascular system and which paves a pathway for future antibody-based therapies [ 109 , 111 , 112 , 113 , 114 ].…”

Differential Effects of Angiotensin-II Compared to Phenylephrine on Arterial Stiffness and Hemodynamics: A Placebo-Controlled Study in Healthy Humans

“…Our findings are rather descriptive; their interpretation relies on the selected well-established cybernetic and hemodynamic concepts described elsewhere which, however, cannot be confirmed or disproved with this human non-invasive approach [ 5 , 7 ]. The measurement of mechanical and neural baroreceptor sensitivity [ 28 ] and invasive measurements of hemodynamics, microneurographic recordings of vasoconstrictive muscle sympathetic nerve activity combined with pharmacologic baroreflex challenges and measurements of plasma catecholamines, as well as dynamic assessment of microcirculation and of novel markers of endothelial function, might refine the approach and warrant future investigation.…”