Some melanocortin receptors and the accessory protein MRAP1 have been found to interact in novel ways when co-expressed in the same cells following stimulation with either ACTH(1-24) or ?MSH. These interactions have been seen for mammalian, bird, and some bony fish melancorotin receptors. To date this type of analysis has not been done on the amphibian melanocortin receptors, MC1R, MC3R, MC4R, and MC5R. To this end, this study was done on the effects on ligand sensitivity for ACTH(1-24) and ?MSH, when the MC1R, MC3R, MC4R, and MC5R paralogs of the amphibian, Xenopus tropicalis were expressed in Chinese Hamster Ovary cells either in the presence of absence of Gallus gallus (c) MRAP1. Based on previous studies on human MC1R, MC3R, MC4R, and MC5R, the expectation was that the sensitivity to stimulation by ?MSH would be lower for all the X. tropicalis receptors. However, for every X. tropicalis receptor tested, co-expression with cMRAP1 had no negative or positive effect on sensitivity to stimulation by xt?MSH. In a similar manner co-expression of xtMC1R, MC3R, or MC5R with cMRAP1 had no effect, positive or negative, on stimulation with xtACTH(1-24). However, co-expression of xtMC4R with cMRAP1 did lower sensitivity to stimulation by xtACTH(1-24) in a statistically significant manner. To date this type of negative interaction between an MC4R ortholog and an MRAP1 ortholog has not been reported for other vertebrates.