Neurotrophin-3 (NT-3) can negatively modulate trkA and associated phenotype in intact sensory neurons, while positively regulating trkC and associated phenotype. How NT-3 effects this response is not clear. Whether NT-3 exerts a differential influence on levels of activated ERK1/2 signaling in trkA- versus trkC-mRNA-positive subpopulations of neurons and the role that the common neurotrophin receptor, p75NTR, plays in this response was assessed by examining alterations in the levels of phospho-ERK1/2 immunofluorescence signal over nuclei of sensory neurons expressing trkA alone, trkC alone, or both trkA and trkC mRNA. NT-3 intrathecal infusion differentially modulated nuclear phospho-ERK1/2 levels detected over neurons expressing trkA alone or trkC alone. Levels were significantly decreased over nuclei of neurons expressing trkA alone and significantly increased over the nuclei of neurons expressing trkC alone. Neurons expressing both trkA and trkC or neurons expressing neither trkA nor trkC had no significant alteration in phospho-ERK1/2. Antisense oligonucleotides directed against p75NTR were infused intrathecally with or without NT-3 infusion to examine the impact of suppressing p75NTR expression on the ability of NT-3 to diminish phospho-ERK1/2 signaling in neurons expressing only trkA. NT-3 did not significantly attenuate levels of phospho-ERK1/2 when p75NTR expression was suppressed by antisense infusion, despite being able to do so when NT-3 was infused alone. In conclusion, NT-3's ability to negatively modulate ERK1/2 signaling in a p75-dependent manner in sensory neurons that express trkA to the exclusion of trkC provides a feasible mechanism by which it negatively modulates other aspects of nociceptive phenotype in these neurons. J. Comp. Neurol. 516:49–58, 2009. © 2009 Wiley-Liss, Inc.