Schild analysis of the interaction between parthenolide and cocaine suggests an allosteric relationship for their effects on planarian motility

The freshwater planarian is an emerging animal model in neuropharmacology due to its close parallels with the nervous system of vertebrates. Cocaine is a naturally occurring compound and an abused drug, as well as the ‘founding member’ of the local anesthetic family. Sesquiterpene lactones of the parthenolide class are naturally occurring products that act as behavioral and physiological antagonists of cocaine in planarians and rats, respectively. One of the best-characterized planarian behaviors induced by various compounds is the change in locomotor velocity. Previous work from our laboratory showed that both parthenolide and cocaine reduced planarian motility and that parthenolide reversed the cocaine-induced motility decrease at concentrations where parthenolide does not affect the movement of the worms. However, the exact mechanism of the cocaine/parthenolide antagonism is unknown. Here, we report the results of a Schild analysis to explore the parthenolide/cocaine relationship in the planarian Girardia tigrina. The Schild slopes of the Δ parthenolide ± cocaine and Δ cocaine ± parthenolide were -0.33 and -0.43, respectively. These slopes were not statistically different from each other, and both were statistically different from -1, suggesting an allosteric relationship between these two compounds. To the best of our knowledge, this is the first study aimed at studying the mechanism of action of the antagonism between cocaine and parthenolide.