The role of neurogenic inflammation and estradiol in migraine: animal experimental data

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A migraine is a neurological condition that can cause various symptoms. Being three times more common in women than men, it has a clear sexual dimorphism, thus estrogen may play an important role in the appearance attacks. Despite continuous progress in migraine research, its exact pathomechanism is still unknown; however, the activation and sensitization of the trigeminal system (TS) play an essential role. One of the animal models developed to mimic the events during migraine is the topical application of inflammatory soup (IS) on the dura mater. We used this method to evaluate various activation and sensitization markers in the trigeminal nucleus caudalis (TNC) and the possible modulatory effect of sumatriptan. a well-known antimigraine drug acting on 5HT1B/1D receptors and kynurenic acid (KYNA), an endogenous molecule of tryptophan metabolism, an N-methyl-D-aspartate (NMDA) antagonist. We also investigated the effect of chronic 17β-estradiol pretreatment on the trigeminal pain-related behavior and activation of trigeminal second-order neurons at the level of TNC in another model of headache, the orofacial formalin test. Compared to placebo the topical IS application on the dura increased the expression of the activation and sensitization markers in the TNC, namely calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid-1 receptor (TRPV1), and neuronal nitric oxide synthase (nNOS), which was attenuated by sumatriptan and KYNA, suggesting the involvement of 5-HT1B/1D and NMDA receptors in the development of neurogenic inflammation and thus in migraine attacks. Our results from the orofacial formalin test demonstrated, that chronic 17β-estradiol treatment had a strong pronociceptive effect on orofacial formalin-induced inflammatory pain, which was demonstrated by both by behavioral changes and increased c-Fos expression in the TNC. This suggests a modulatory action of estradiol on head pain through estrogen receptors, which are present throughout the TS.

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