Melanocortin receptor ligands accelerate functional recovery after peripheral nerve crush. It is not known which mechanism is involved or via which melanocortin receptor this effect occurs, albeit indirect evidence favours the melanocortin MC4 receptor. To test whether the melanocortin MC4 receptor is involved in the effects of melanocortins on functional recovery, we used melanocortin compounds that distinguish the melanocortin MC4 receptor from the melanocortin MC1, MC3 and MC5 receptors on basis of selectivity and agonist/antagonist profile. Activation and binding studies indicated that the previously described peptides JK1 (Ac-Nle-Gly-Lys-D-Phe-Arg-Trp-Gly-NH2) and [D-Tyr4]melanotan-II ([D-Tyr4]MTII. Ac-Nle-c[Asp-His-D-Tyr-Arg-Trp-Lys]NH2) are selective for the rat melanocortin MC4 receptor as compared to the rat melanocortin MC3 and MC5 receptors, but are also potent on the melanocortin MC1 receptor. Both peptides did not accelerate sensory recovery in rats with a sciatic nerve crush, whereas the non-selective melanocortin agonist melanotan-II (MTII, Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]NH2) was effective. The melanocortin MC3/MC4 receptor antagonist SHU9119 (Ac-Nle-c[Asp-His-D-Nal(2)-Arg-Trp-Lys]NH2) also enhanced sensory recovery. This effect was probably not due to interaction with the melanocortin MC4 receptor, since JK46 (Ac-Gly-Lys-His-D-Nal(2)-Arg-Trp-Gly-NH2), a selective melanocortin MC4 receptor antagonist, was ineffective. Taken together, these data suggest that melanocortins do not accelerate sensory recovery via interaction with the melanocortin MC4 receptor. From the known melanocortin receptors, only the involvement of the melanocortin MC5 receptor in acceleration of recovery could not be excluded.