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PD98059 blocks mitogen-activated protein kinase (MAPK) by inhibiting its activator, MAP kinase kinase (MEK). We have previously found that PD98059 only transiently inhibits spontaneous axonal outgrowth from adult mouse dorsal root ganglia (DRG) explants, whereas it causes sustained inhibition of nerve growth factor (NGF)-stimulated growth. Surprisingly, the present results showed that outgrowth stimulation by neurotrophin-3 (NT-3), interacting with another neuronal subgroup, was markedly enhanced by PD98059 and also by U0126, another inhibitor of MAPK activation. In contrast, the effects of glial cell line-derived neurotrophic factor (GDNF), which stimulates still another subgroup of DRG neurons, was opposed by PD98059. Axonal outgrowth in vitro can also be strongly increased by a prior axotomy in vivo. The increased outgrowth in preaxotomized explants was effectively inhibited by the presence of PD98059. Immunocytochemistry based on whole-mount labelling revealed the presence of neuronal MAPK, which was found to be activated by NGF, NT-3, and GDNF in separate axonal populations and by a prior axotomy in a majority of growing axons. The results suggest that there are important differences in the NGF and NT-3 signalling pathways, which may involve positive and negative control mechanisms by MAPK activation, respectively. Other findings indicate that GDNF exerts its growth effects by activation of MAPK and that expression of the conditioning effect in vitro in preaxotomized preparations also requires activation of MAPK.