Corticosteroid-dependent increased expression of CGRP and its receptor subunits within the rodent trigeminal ganglion does not prompt cephalic allodynia.

BackgroundCalcitonin gene-related peptide (CGRP) has a causative role in migraine pathogenesis but its effects on trigeminal afferents are still unclear. Corticosteroids represent a very useful tool in headache therapy with an unknown mechanism of action. Despite the widespread effects of corticosteroids on gene transcription, whether they regulate CGRP expression within the trigeminovascular system remains to be investigated.MethodsThe effects of dexamethasone on expression of CGRP and its receptor subunits receptor activity-modifying protein (RAMP1) and calcitonin receptor-like receptor (CLR) have been evaluated in rat thyroid parafollicular CA77 and human neuroblastoma SHSY-5Y cell cultures, as well as in isolated human peripheral blood mononuclear cells. The effects of dexamethasone on the rat and human CGRP promoter were also evaluated. In vivo, rats and mice were treated with betamethasone (320 µg/kg for 10 days) to investigate whether the drug altered the expression of CGRP, RAMP1 and CLR in the trigeminal ganglion (TG). We also evaluated the effect of betamethasone on CGRP mRNA stability and release from the mouse TG, as well as on mouse spontaneous or nitroglycerin-induced cephalic allodynia.ResultsWe report that dexamethasone triggered transcriptional activation of the rat and human CGRP gene, also increasing transcript levels of RAMP1 but not of CLR in cultured cells. These effects were paralleled in the TG of rats and mice challenged with betamethasone, with mice also showing increased expression levels of CLR. Of note, although a 13-fold increase of the CGRP releasable pool occurred in the TG of betamethasone-treated mice, the animals were not sensitized to cephalic allodynia.ConclusionsIn keeping with the emerging immunosuppressing effects of CGRP, corticosteroids increase its expression in rat and human cell lines, as well as in rodent TG. Evidence that a substantial increase of releasable CGRP in the TG does not reduce orofacial pain thresholds suggests that basal release of endogenous CGRP differs from its exogenous administration in terms of trigeminal afferent sensitization.