Alpha-melanocyte stimulating hormone (alpha MSH) and Org 2766 (an adrenocorticotrophic hormone (ACTH) MSH4-9 analogue) stimulate sprouting after nerve damage in vivo. In cultures of rat spinal cord cells only alpha MSH enhances neurite outgrowth. In order to analyse the mode of action of alpha MSH and to get a clue why its action differs from that of Org 2766, we studied whether expression of c-fos was induced in spinal cord cells by treatment with alpha MSH or Org 2766. We found a rapid and transient induction of both c-fos mRNA and protein after treatment with 100 microM alpha MSH. Treatment with Org 2766 (100 pM-100 microM) had no effect on c-fos expression. These results suggest that c-fos is involved in the signal transduction system of alpha MSH stimulated neuronal outgrowth in vitro.