Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation
Hugo R. Arias, Laura Micheli, Deborah Rudin, Ophélie Bento, Saskia Borsdorf, Clara Ciampi, Philippe Marin, Evgeni Ponimaskin, Dina Manetti, María Novella Romanelli, Carla Ghelardini, Matthias E. Liechti, Lorenzo Di Cesare Mannelli
Abstract
The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT 2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT 2A, 5-HT 6 , and 5-HT 7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se , supporting the concept that 5-HT 2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT 2A and 5-HT 6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT 7 receptor. Considering previous studies showing that 5-HT 6 receptor inhibition, but not activation, and 5-HT 7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT 2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT 2A receptor activation. • Ibogalogs such as DM506 and IBG decrease neuropathic and visceral pain in mice. • Ibogalogs activate both 5-HT 2A and 5-HT 6 receptor subtypes. • DM506 and IBG, but not TBG, act as inverse agonists of the 5-HT 7 receptor. • Pain-relieving effects of ibogalogs are mainly mediated by 5-HT 2A receptor activation. • Pain-relieving effects of ibogalogs are blocked by the 5-HT 2 receptor antagonist ketanserin.