To facilitate an understanding of injury-induced changes within the nervous system, we used a single-cell, in vitro model of axonal injury. Sensory neurons were individually dissociated from the central nervous system (CNS) of Aplysia and placed into cell culture. The major neurite of some neurons was then transected (Axotomized neurons). Axotomy in hemolymph-containing culture medium produced long-term hyperexcitability (LTH-E) and enhanced neuritic sprouting (long-term hypermorphogenesis [LTH-M]). Axotomy in the absence of hemolymph induced LTH-E, but not LTH-M. Hemolymph-derived growth factors may activate tyrosine receptor kinase (Trk) receptors in sensory neurons. To examine this possibility, we treated uninjured (Control) and Axotomized sensory neurons with K252a, an inhibitor of Trk receptor activity. K252a depressed the excitability of both Axotomized and Control neurons. K252a also produced a distinct pattern of arborizing outgrowth of neurites in both Axotomized and Control neurons. Protein kinase C (PKC) is an intracellular signal downstream of Trk; accordingly, we tested the effects of bisindolylmaleimide I (Bis-I), a specific inhibitor of PKC, on the axotomy-induced cellular changes. Bis-I blocked LTH-E, but did not disrupt LTH-M. Finally, because Trk activates the extracellular signal regulated kinase (ERK) pathway in Aplysia sensory neurons, we examined whether this pathway mediates the injury-induced changes. Sensory neurons were axotomized in the presence of U0126, an inhibitor of mitogen-activated/extracellular receptor-regulated kinase (MEK). U0126 blocked the LTH-M due to axotomy, but did not impair LTH-E. Therefore, distinct cellular signaling pathways mediate the induction of LTH-E and LTH-M in the sensory neurons.