Neurotrophic factors are molecules that prevent neuronal degeneration and regulate neuronal phenotype during either development or adulthood. Relatively little is known about the comparative responsiveness of injured adult central nervous system motor neurons to various neurotrophic factors. In the present study we examined the effects of four members of the neurotrophin family on injured adult motor neurons. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4/5 were infused intracerebroventricularly into adult rats following transection of the motor hypoglossal nerve. Two weeks after axotomy, brain-derived neurotrophic factor and neurotrophin-4/5 completely prevented the loss of the cholinergic phenotype in hypoglossal motor neurons (97 +/- 11% and 99 +/- 5%, respectively) as assessed by choline acetyltransferase immunolabeling. In contrast, nerve growth factor and neurotrophin-3 exerted no protective effect. The low-affinity p75 neurotrophin receptor, capable of binding all four neurotrophins, was re-expressed in injured hypoglossal neurons; the majority of injured hypoglossal neurons also express trkB receptors but not trkA or trkC receptors. Thus, injury-induced responses to neurotrophins in adult motor neurons are mediated by trk receptors and their agonists, but may or may not also require low-affinity p75 neurotrophin receptors. Intracerebroventricular infusions of trkB agonists may be a useful means of targeting multiple and distantly separated populations of motor neurons for neurotrophic factor therapy.