Peptides related to melanotropin (alphaMSH) and corticotropin (ACTH), collectively termed melanocortins, are known to improve the postlesion repair of injured peripheral nerves. In addition, melanocortins exert trophic effects on the outgrowth of neurites from central nervous system neurons in vitro. Here we report, for the first time, the stimulation by alpha-MSH of spinal neurite outgrowth in vivo after injury. In the in vivo model, spinal cord trauma was produced at lower thoracic spinal levels of adult rats. Under a surgical microscope a laminectomy was performed exposing the dorsum of the spinal cord. Then the dura was cut longitudinally and the dorsal columns were identified. Iridectomy scissors were used to transect the dorsal half of the spinal cord bilaterally, thereby completely lesioning the main corticospinal tract component. Then the lesion gap was immediately filled with a solid collagen matrix. Ingrowth of fibers was quantified using an advanced image analyser using a video image of sections transmitted by a camera. In the control situation virtually no ingrowth of sprouting injured fibers into the collagen implant in the lesion gap was seen. However, when the collagen matrix contained 10(-8) M alpha-MSH, a profound and significant stimulation of fiber ingrowth into the implant was observed (alpha-MSH, 21.5 +/- 2.9%; control, 1.4 +/- 0.6% p < 0.01). A small percentage of these ingrowing fibers was CGRP-immunoreactive (17.0 +/- 4%), whereas no serotonergic ingrowth was observed. Furthermore, we found that local application of alpha-MSH directs a substantial amount of lesioned anterogradely labelled corticospinal tract axons to regrow into the collagen implant (alpha-MSH, 15.2 +/- 5.2%; control, 0.5 +/- 0.3%, p < 0.01). The observed fiber ingrowth is not accompanied by an invasion of astroglial or reactive microglial cells into the implant. In conclusion, inclusion of alpha-MSH in the collagen implant stimulates the regrowth of injured axons in the adult rat spinal cord.