Abstract
BackgroundCalcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification. Here, we investigated the role of CGRP in an animal model that mimics the chronic migraine condition via repeated and intermittent nitroglycerin (NTG) administration. We also evaluated the modulatory effect of topiramate on this experimental paradigm. Male Sprague-Dawley rats were injected with NTG (5 mg/kg, i.p.) or vehicle, every 2 days over a 9-day period (5 total injections). A group of animals was injected with topiramate (30 mg/kg, i.p.) or saline every day for 9 days. Twenty-four hours after the last administration of NTG or vehicle, animals underwent tail flick test and orofacial Von Frey test. Rats were subsequently sacrificed to evaluate c-Fos and CGRP gene expression in medulla-pons region, cervical spinal cord and trigeminal ganglia.ResultsNTG administration induced spinal hyperalgesia and orofacial allodynia, together with a significant increase in the expression of CGRP and c-Fos genes in trigeminal ganglia and central areas. Topiramate treatment prevented NTG-induced changes by reversing NTG-induced hyperalgesia and allodynia, and inhibiting CGRP and c-Fos gene expression in all areas evaluated.ConclusionsThese findings point to the role of CGRP in the processes underlying migraine chronification and suggest a possible interaction with gamma-aminobutyrate (GABA) and glutamate transmission to induce/maintain central sensitization and to contribute to the dysregulation of descending pain system involved in chronic migraine.
Highlights
Calcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification
Chronic NTG administration caused a state of hyperalgesia, which was detected as a reduction in the latency at the tail flick test performed on day 10 as compared with both baseline value and CT group
Chronic and intermittent NTG administration caused orofacial allodynia with a reduction in the mechanical pain threshold compared to the baseline value and to mRNA expression of CGRP and c-Fos genes NTG administration induced a significant increase in the expression of c-Fos and CGRP mRNA in the medulla-pons region, cervical spinal cord and trigeminal ganglia (Fig. 3)
Summary
Calcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification. We investigated the role of CGRP in an animal model that mimics the chronic migraine condition via repeated and intermittent nitroglycerin (NTG) administration. Rats were subsequently sacrificed to evaluate c-Fos and CGRP gene expression in medulla-pons region, cervical spinal cord and trigeminal ganglia. Monoclonal antibodies directed against CGRP have proved effective in the preventive treatment of chronic migraine [11]. The precise mechanisms and sites where CGRP may act to favor chronification of migraine are still to be identified. Topiramate is an antiepileptic drug with established efficacy in chronic migraine prevention [13, 14]. The drug likely acts on the cell excitatory mechanisms via its influence on the receptor/channel protein complexes [15,16,17]
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