Dramatic changes occur in neuropeptide expression in sensory and sympathetic neurons following axonal injury. Based on the finding that the cytokine leukemia inhibitory factor (LIF) plays an important role in mediating these changes in sympathetic neurons, its participation in triggering changes in sensory neurons was examined. By the use of transgenic mice in which the LIF gene had been knocked out, LIF was found to contribute to the induction of galanin expression in dorsal root ganglia (DRG) after sciatic nerve lesion. On the other hand, two other neuropeptide changes that occur in DRG under these conditions, the reduction of substance P and induction of neuropeptide Y, were independent of LIF expression. In the sympathetic superior cervical ganglion, transection of the postganglionic nerves close to the ganglion resulted in a rapid induction of LIF mRNA in the ganglion and in the lesioned nerve trunk. In contrast, transection of the sciatic nerve close to or distant from the DRG caused a rapid induction of LIF mRNA in the lesioned nerve, but not in the DRG. DRG were capable of making substantial amounts of LIF mRNA when placed in explant cultures, but, in vivo, only a slight induction was found even when both central and peripheral nerve processes of these sensory neurons were transected. These latter observations suggest that, in contrast to the superior cervical ganglia, the DRG environment inhibits the lesion-induced expression of LIF in vivo and/or explanted DRG produce stimulatory signals not found in vivo. Together with the data on the induction of galanin, these observations provide evidence that LIF, generated at a site at some distance from the ganglion, is involved in triggering part of the cell body reaction in sensory neurons.