Three experimental models of axonal injuries in adult rat spinal motoneurons were established to investigate changes of gene expression in response to such injuries. We took advantage of cDNA microarray analysis to determine the differential expression of genes in injured motoneurons following distal axotomy or root avulsion in the absence or presence of BDNF. The major finding was that, in response to proximal axonal injury (avulsion), expression of genes that are known to facilitate neuronal survival and axonal regeneration (e.g., IGFRII, PI3K, IGFBP-6, GSTs, GalR2) were down-regulated; but following treatment with BDNF they were up-regulated. In addition, the expression of genes known to be involved in apoptosis and DNA damage (e.g., ANX5, TS, ALR) were down-regulated in BDNF-treated animals with avulsion. Furthermore, many functional families of genes previously shown to play roles in the pathophysiology of axonal injury, including SNAP-25A, SV2B, Ras-related ras3a/4b, ERK1/2, 14-3-3 proteins, proteasome proteins, oncogenes, GAP-43, and NMDAR1, were altered after either distal axotomy or avulsion injury. Some of the changes in gene expression, including Lim-2, FRAG1, GlaR2, GSTs, ALR, TS, ANX3/5, and nhe1/2, are first reported here in injured motoneurons. The differential expression of genes identified by the expression arrays was confirmed by gene-specific RT-PCR for eight genes (GAP-43, IGFR II, Lim-2, MIF, NDAP1, TS, PCC3, and FRAG1) and by in situ hybridization for Lim-2. These results suggest that abnormal regulation of particular biochemical pathways may induce motoneuron death after ventral root avulsion in adult animals. This study presents an approach for selecting specific genes and their products that may be involved in motoneuron degeneration following axonal injuries.