Following injury to their peripheral branches, mechanosensory neurons in Aplysia display long-term plasticity that is expressed as soma hyperexcitability, synaptic facilitation, and neurite outgrowth. To investigate the nature of signals that convey information about distant axonal injury, we have investigated the development of injury-induced soma hyperexcitability in two in vitro preparations. In isolated ganglia, proximal nerve crush caused hyperexcitability to appear sooner than did distal crush, and the difference in development of hyperexcitability indicated that the injury signal moved at a rate (36 mm/d) similar to previously reported rates of retrograde axonal transport in this animal. This hyperexcitability was not due to interruption of continuous retrograde transport of trophic substances (a negative signal) because inhibitors of axonal transport applied to uncrushed nerve segments did not induce hyperexcitability. Indeed, inhibitors of axonal transport blocked crush-induced hyperexcitability, indicating that positive injury signals are involved. Crush-induced hyperexcitability was unaffected by bathing the nerve in tetrodotoxin or the ganglion in Cd2+, suggesting that the retrograde signals depend upon neither spike activity in the nerve nor synaptic transmission in the ganglion. Close excision of sensory neuron somata (which largely eliminated delays attributable to axonal transport) produced soma hyperexcitability that was expressed after 10 hr and lasted at least 17 d. These data indicate that axonal injury mobilizes signal molecules that are conveyed by retrograde axonal transport into the soma and possibly the nucleus, where they induce long-term plasticity similar to that expressed by these cells during learning and memory.