Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation

• Published in: Biomedicine & pharmacotherapy 2024-08, Vol.177, p.116867, Article 116867
• Main Authors: Arias, Hugo R., Micheli, Laura, Rudin, Deborah, Bento, Ophelie, Borsdorf, Saskia, Ciampi, Clara, Marin, Philippe, Ponimaskin, Evgeni, Manetti, Dina, Romanelli, Maria Novella, Ghelardini, Carla, Liechti, Matthias E., Di Cesare Mannelli, Lorenzo
• Format: Article
• Language: English
• Subjects: 5-HT2A; 5-HT6; agonist and reverse agonist; and 5-HT7 receptors; ibogalogs; Life Sciences; Neurons and Cognition; neuropathic pain; Pharmaceutical sciences; Pharmacology; Visceral pain
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.116867

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-HT2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT2A, 5-HT6, and 5-HT7 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-HT2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT2A and 5-HT6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT7 receptor. Considering previous studies showing that 5-HT6 receptor inhibition, but not activation, and 5-HT7 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-HT2B/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-HT2A receptor activation. [Display omitted] •Ibogalogs such as DM506 and IBG decrease neuropathic and visceral pain in mice.•Ibogalogs activate both 5-HT2A and 5-HT6 receptor subtypes.•DM506 and IBG, but not TBG, act as inverse agonists of the 5-HT7 receptor.•Pain-relieving effects of ibogalogs are mainly mediated by 5-HT2A receptor activation.•Pain-relieving effects of ibogalogs are blocked by the 5-HT2 receptor antagonist ketanserin.