Ibogalogs reduce acute and chronic headache-like behaviours in rodents by different co-modulatory mechanisms involving 5-HT1 and 5-HT2 receptor subtypes.

The main objective of this work is to assess whether ibogalogs decrease headache-like behaviors in rats using the cortical spreading depression (CSD) and medication overuse headache (MOH) models. The CSD and MOH results showed that tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506) significantly decreased allodynia induced by acute injection of KCl or repetitive administration of sumatriptan. The effect of ibogalogs in the CSD model was sex-independent. The observed effects lasted 6-8 h, with TBG showing comparatively higher efficacy in both models. We also assessed the potential role of serotonin type 2 receptor (5-HT2R) and 5-HT1B/1DR subtypes the effects of ibogalogs using selective antagonists such as ketanserin and GR127935, respectively. The antagonist effects were headache type-dependent: in acute headache, GR127935 inhibited ibogalogs' activity during the first hour but subsequently enhanced their effects, whereas ketanserin enhanced their activities; in chronic headache, GR127935 abolished ibogalog's effects during the first 3 h, whereas ketanserin inhibited IBG's effect during the first 2 h but enhanced TBG's effect. These results suggested that the antiheadache effects of ibogalogs are mediated by co-modulation of 5-HT1R and 5-HT2R subtypes. The functional results showed the ibogalogs activate 5-HT1R subtypes with the following selectivity: 5-HT1FR ~ 5-HT1DR > 5-HT1BR >> 5-HT1ER. Thus, we compared the activity of ibogalogs between wild type (WT) and 5-HT1FR knockout (KO) mice in the MOH model. The results in WT mice showed that ibogalogs increase the facial withdrawal threshold with the following efficacy: TBG > IBG > DM506. Moreover, ibogalog antiallodynic effects were reduced in KO mice after 4 h, supporting a role for the 5-HT1FR in the actions of ibogalogs in headache attenuation. In conclusion, ibogalogs significantly reduce acute and chronic headache-like behaviors by a co-modulatory mechanism between 5-HT1R and 5-HT2R subtypes.