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-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.
摘要：
这项研究的目的是确定源自iboga生物碱的新型非致幻化合物的抗超敏反应活性（即，ibogalogs)，包括tabernanthalog(TBG)，ibogainalog(IBG),和ibogaminalog(DM506)，使用神经病（慢性缩窄损伤；CCI）和内脏疼痛（葡聚糖硫酸钠；DSS）的小鼠模型。Ibogalogs以剂量和时间框架依赖性方式降低了CCI引起的机械性痛觉过敏和异常性疼痛，其中IBG在相对较低的剂量下表现出最长的抗痛觉过敏活性，而DM506显示最快的响应。这些化合物还降低了结肠炎引起的超敏反应，其中DM506表现出最长的活性。为了了解这些影响的机制，使用了两种方法：ibogalogs用5-HT2A受体拮抗剂ketanserin挑战，这些化合物的药理活性在各自的5-HT2A进行了评估，5-HT6和5-HT7受体亚型。行为结果清楚地表明，ketanserin消除了ibogalogs的疼痛缓解活性，而本身没有任何作用，支持5-HT2A受体激活的概念，但不是抑制，参与了这个过程。功能结果表明，ibogalogs有效激活5-HT2A和5-HT6受体亚型，而它们在5-HT7受体上表现为反向激动剂（TBG除外）。考虑到以前的研究表明5-HT6受体抑制，但不是激活，和5-HT7受体激活，但不是抑制，缓解慢性疼痛，我们可以放弃这两种受体亚型参与ibogalogs的疼痛缓解活动。还排除了5-HT2B/2C受体亚型的潜在参与。总之,ibogalogs在小鼠中的抗超敏反应活性是由涉及5-HT2A受体激活的机制介导的。
