Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT_2A and mGlu₂ receptors

The objective of this study was to determine the anti-neuropathic activity of a variety of ibogalogs, including tabernanthalog (TBG), ibogaminalog (DM506), ibogainalog (IBG), nor-IBG, catharanthalog (CAG), and PNU-22394 using the oxaliplatin (OXA) neuropathic pain model in mice, and to investigate whether there is crosstalk between the 5-HT_2A and mGlu₂ receptors. All tested ibogalogs induce pain-relieving activity using both cold plate and paw pressure tests, without toxic effects. The most potent ibogalogs were IBG and CAG, whereas nor-IBG and DM506 were the longest-acting compounds. The anti-neuropathic activity of ibogalogs was inhibited by ketanserin, a 5-HT_2A receptor antagonist, indicating a role for the 5-HT_2A receptor for these effects. Sub-threshold doses of IBG (1 mg/kg) and nor-IBG (3 mg/kg) produced pain relief only in the presence of a sub-threshold dose of LY379268, a selective mGlu₂ receptor agonist, indicating that signaling through both 5-HT_2A and mGlu₂ receptors improves efficacy. In the functional study using HEK293 cells co-expressing both 5-HT_2A and mGlu₂ receptors, Glu increased the apparent potency of ibogalogs in a concentration-dependent manner and sub-threshold concentrations of ibogalogs augmented the Glu-induced response through the mGlu₂ receptor, which collectively indicate functional crosstalk between both receptors. Ibogalogs increased mGlu₂ receptor phosphorylation on Ser⁸⁴³, a proposed key molecular event underlying the functional receptor crosstalk. Our study shows for the first time that diverse ibogalogs induce anti-neuropathic activity through a synergic mechanism involving both 5-HT_2A and mGlu₂ receptors.