France Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
Institut de Cancérologie de l'Ouest Paul Papin, 15 rue André Boquel-49055 Angers, France.
Toxins (Basel). 2019 Sep 4;11(9):516. doi: 10.3390/toxins11090516.
Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis. Several cellular mechanisms and different targets have been proposed to account for the analgesic effect of the toxin, such as nerve degeneration, the inhibition of inflammatory mediators and the activation of angiotensin II receptor 2. In this review, we discuss the current knowledge in the field, highlighting possible controversies. We first discuss the different pain-mimicking experimental models that were used to study the effect of mycolactone. We then detail the different variants of mycolactone that were used in such models. Overall, based on the results and the discussions, we conclude that the development of mycolactone-derived molecules can represent very promising perspectives for new analgesic drugs, which could be effective for specific pain indications.
疼痛目前是患者寻求医疗关注最常见的症状。现有的治疗方法效果有限，且副作用明显。此外，大多数情况下，镇痛的持续时间很短。如今，疼痛处理仍然是一个重大挑战。从大自然中寻找新的强效镇痛药是一个很有前途的选择；在这方面，详细研究布吕利溃疡（一种由细菌引起的传染性疾病，其特征是无痛性溃疡性病变）中实施的令人着迷的镇痛作用，似乎特别有希望。更确切地说，在这种疾病中，无痛性皮肤溃疡是由放线菌酮引起的，放线菌酮是一种聚酮内酯外毒素。事实上，放线菌酮除了具有镇痛作用外，还对宿主产生广泛的影响，因为它被证明可以调节免疫反应或引起细胞凋亡。已经提出了几种细胞机制和不同的靶点来解释毒素的镇痛作用，例如神经退化、抑制炎症介质和激活血管紧张素 II 受体 2。在这篇综述中，我们讨论了该领域的现有知识，强调了可能存在的争议。我们首先讨论了用于研究放线菌酮作用的不同疼痛模拟实验模型。然后，我们详细介绍了用于此类模型的不同变体的放线菌酮。总的来说，根据结果和讨论，我们得出结论，放线菌酮衍生分子的开发可能为新型镇痛药的开发带来非常有前景的前景，这些药物可能对特定的疼痛适应症有效。
