A routine toxicity test of the alkaloid extract from the Ecuadoran poison frog Epipedobates anthonyi gave a Straub-tail (S-T) response on sub-cutaneous (sc) injection in mice, a phenomenon never seen before from any poison frog alkaloid. It is characteristic of opioids; however, in this instance it was not blocked by a morphine-antagonist, naloxone. Its site of action was soon shown to be a nicotinic receptor. The determination of the structure of this novel analgesic named epibatidine has led to a renaissance of research into controlling pain via nicotinic pathways (thereby minimizing the risk of tolerance/addiction) and the synthesis of many analogs, some of which are discussed.