Activity of Nonhallucinogenic Ibogalogs on Chemotherapy-Induced Peripheral Neuropathic Pain in Mice

In this study, we examined the effects of ibogaminalog (DM506), a nonhallucinogenic analog of ibogamine, in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) induced by paclitaxel. We also assessed the effects of tabernanthalog (TBG) and investigated the potential role of serotonin receptor subtype 2A (5-HT_2AR) for both compounds. DM506 and TBG demonstrated antinociceptive activity in the CIPN model. DM506 produced a more prolonged effect, lasting between 10 and 14 days, with nociception reduction in mechanical (von Frey) and cold (acetone) hypersensitivity assays. These effects were observed in a dose- and time-dependent manner. Unlike some previous studies that reported effects lasting only hours, the effects we observed persisted for several days. Furthermore, neither compound produced long-lasting effects on locomotor activity, even at relatively high doses. The antinociceptive effects of both compounds in the CIPN mouse model were blocked by the 5-HT_2AR selective antagonist volinanserin. In vitro studies revealed that DM506 does not block cytokine/chemokine expression in microglial cells but partially protected dorsal root ganglion (DRG) neurons treated with paclitaxel in the 100-300 nM concentration range in a volinanserin-sensitive manner. We conclude that DM506 and TBG possess antinociceptive properties in mice via pathways involving 5-HT_2AR activation. Although it is unlikely that this effect involves anti-inflammatory activity in microglia, partial neuroprotective activity in DRG neurons can be considered.