Using in situ hybridization histochemistry and immunohistochemistry, the present study examines the cooperative regulation of transcription of molecules involved in the Ras-signal and the cAMP dependent protein kinase (PKA) pathways during peripheral nerve regeneration in rats. Injury to hypoglossal motor neurons resulted in an increase in extracellular regulated kinase (ERK, or MAP kinase) and ERK kinase (MEK, or MAP kinase kinase) mRNAs, but in a decrease in the expression of the catalytic subunits of PKA (C alpha and C beta) mRNAs. These results show the importance of the Ras-signal pathway in the nerve regeneration process and extend recent observation which suggested a cross-talk between the Ras and PKA pathways in vitro. The down-regulation of PKA may facilitate the activation of the Ras pathway which is located downstream of the growth factor receptor. The present study may suggest a possibility of regulatory talk between these two major signal transduction pathways.