Activating transcription factor-3 (ATF3) is a member of the ATF/CREB transcription factor superfamily and is induced in dorsal root ganglion (DRG) cells after nerve injury. In order to study the regulation of ATF3, we have examined the effect of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on ATF3 expression. In untreated rats, sciatic nerve transection induced ATF3 immunoreactivity in 82% of L4 DRG cells at 14 days after axotomy. Intrathecal delivery of NGF or GDNF for 2 weeks commencing immediately after injury reduced the ATF3 expression to 35 and 23% of DRG cells, respectively. Cell size analysis indicated that NGF had protected a population of mainly small- to medium-sized cells, but that the GDNF had protected a population of both small and large cells. This effect was confirmed by double labelling for P2X3, CGRP and 200 kDa neurofilament, markers for small peptide-poor cells, peptide-rich cells and large cells, respectively. Thus GDNF reduced the percentage of ATF3-immunoreactive P2X3 cells from 70 to 4%, and the percentage of ATF3-immunoreactive neurofilament cells from 63 to 24%. NGF was less effective than GDNF in reducing ATF3 expression in these cell types, but reduced the percentage of ATF3-immunoreactive CGRP cells from 10% to < 1%. These results show that ATF3 expression in specific populations of DRG cells can be modulated by exogenous supplementation of specific trophic factors, and suggest that ATF3 expression may normally be induced by the loss of target-derived NGF and GDNF.