alpha-Melanocyte-stimulating hormone (alpha-MSH) accelerates the regrowth of peripheral nerve axons in the rat following their transection (Verhaagen et al., Expl Neurol. 92, 451-454, 1986). The cellular mechanisms of this trophic response were investigated for several naturally occurring derivatives of alpha-MSH using Nerve Growth Factor (NGF)-stimulated quail sensory ganglion explants in vitro in which both neurite outgrowth and non-neuronal cell behaviour could be more reliably observed and quantified. Neurite outgrowth was determined with a semi-quantitative scoring assay. Glial migration into the outgrowth was quantified using a monoclonal antibody, GTE-52, which labels the nuclei of Schwann cells. Des-acetyl alpha-MSH caused a marginal increase in the neurite outgrowth density which was significant at concentrations of 0.04 and 0.1 microgram/ml. The response to acetylated (N-acetyl, N,O-diacetyl) forms of alpha-MSH was characterized by fascicle formation by neurites which resulted in an apparent decrease in the neurite score, and by the outgrowth of non-neuronal cells. Using monoclonal antibody GTE-52, which recognizes a glial nuclear antigen, these cells were identified as Schwann cells. N-Acetyl, but not des-acetyl alpha-MSH increased the number of GTE-52-labelled cells in the NGF-stimulated neurite outgrowth and stimulated their migration in the absence of neurites when NGF was omitted from the culture medium. Exposure of growing explants to two polyclonal antibodies against alpha-MSH resulted in an increased neurite outgrowth density. The results support the hypothesis that alpha-MSH peptides stimulate peripheral nerve growth by modulating the neurite sprouting response, and demonstrate that the nature of the neurotrophic response to naturally occurring melanotropins depends on the existence of acyl substitution at the N-terminal amino acid residue. A possible role of endogenous melanotropin peptides in the regulation of sensory nerve growth is discussed.