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 Mycobacterium ulcerans 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.