Activation pattern and modulation of pain related structures in animal models of migraine

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Summary Migraine is a common neurological disorder with a high social burden and unknown pathomechanism. The trigeminal systems plays a crucial part in the pathological processes of the disease, therefore the knowledge about the functioning and modulation options of this system is essential for developing new therapeutic options against this condition. One of the animal models used in migraine research is the electrical stimulation of the trigeminal ganglion (ESTG). In this model we examined the activation pattern of the brain stem nuclei, previously regarded as migraine generators in human studies. To find new targets modulating the trigeminal nociceptive pathway we examined the effects of Brilliant Blue G-250 (BBG) and probenecid (PROB) on the number of c-Fos immunoreactive cells and on the changes in calcitonin gene-related peptide and neuronal nitric oxide synthase immunoreactivity in the caudal trigeminal nucleus. BBG is a P2X7 receptor antagonist, which receptors were previously shown to be involved in nociceptive processing. PROB is an inhibitor of numerous organic anion transporters and multidrug resistance-associated proteins, and was proposed to be antinociceptive. BBG was tested in the ESTG model in two stimulation paradigms, a mild and a robust one, and in the orofacial formalin test, while PROB was tested in the formalin test only. After ESTG the activation pattern of the brainstem nuclei was not similar to the pattern seen during migraine attacks in human functional studies, suggesting that the activation of the trigeminal system in the rat does not lead to the activation of the migraine generator nuclei. BBG was effective in decreasing the activation of the second order trigeminal neurones only in the robust stimulation paradigm of ESTG, which suggest that P2X7 receptors more likely play a fine-tuning role in of the trigeminal system, and are not general modulators. PROB had a clear antinociceptive behavioural effect and was able to decrease trigeminal activation after formalin, suggesting that one or even more of its molecular targets play a crucial part in trigeminal nociceptive processing. Our results provide important information about the functioning of the trigeminal system, thus contribute to the understanding of pathological processes underlying headache and migraine.

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