Exposure of neuronal terminals to target-derived NGF has been hypothesized to regulate cell body responses at a distance. To test this hypothesis and, more specifically, to determine whether NGF distally regulates the synthesis of its two characterized receptors, we developed the following paradigm. Sympathetic neurons of the superior cervical ganglion (SCG) that project either to the eye or to the ear were labeled, in adult animals, with the retrograde tracers Fast Blue and Fluoro-Gold, respectively. NGF was then injected daily into the anterior chamber of one eye, exposing the terminals of the ipsilateral eye neurons to increased NGF. To control for systemic and/or localized injury effects, cytochrome C or PBS were injected into the contralateral eye of the same animals. In situ hybridization and image analysis were then used to determine neuronal levels of p75 NGF receptor, trkA, and T alpha 1 alpha-tubulin mRNAs, with the latter providing a correlative measure of neuronal sprouting. Morphological measurements revealed that exogenous, terminally-derived NGF increased the mean cross-sectional area of eye neurons by 37%. Grain counts for p75 NGF receptor mRNA increased from 2- to 6-fold in the NGF-treated neurons, and grain densities, which accounted for neuronal hypertrophy, also increased significantly. In contrast, grain counts for trkA mRNA were not significantly increased by this treatment, while T alpha 1 alpha-tubulin mRNA levels increased only 1.5- to 2-fold. No increase in grain density was detected for either of these mRNAs. The NGF-induced increased in p75 NGF receptor mRNA levels was accompanied by terminal sprouting and by an increase in the density of p75 NGF receptors on terminal neurites, as indicated by IgG-192 immunostaining of the NGF-treated iris. These data therefore suggest that, in addition to promoting local sprouting, increased target-derived NGF increases the levels of p75 NGF receptor relative to trkA on terminal neurites, by differentially regulating receptor synthesis. Such a direct regulatory feedback loop may well play an integral role in precisely modulating neuronal responses as a function of the amount of available trophic support and/or target tissue.