In the central nervous system, regeneration of injured axons and sprouting of intact axons are suppressed by myelin-derived molecules that bind to the Nogo receptor (NgR). We used a soluble form of the NgR (sNgR), constructed as an IgG of the human NgR extracellular domain, to manipulate plasticity of uninjured primary afferent and descending monoaminergic projections to the rat spinal cord following dorsal rhizotomy. Rats with quadruple dorsal rhizotomies were treated with intrathecal sNgR or saline, or were left untreated for 2 weeks. Rhizotomy alone resulted in sprouting of serotonergic axons and to a lesser extent, tyrosine-hydroxylase (TH)-expressing axons, while axons expressing dopamine-beta-hydroxylase (DbetaH) were unaffected. Human IgG immunohistochemistry revealed that sNgR infused into the intrathecal space penetrated approximately 300 microm into spinal white and grey matter. Separate axonal populations differed in their responses to intrathecal sNgR: TH-expressing and DbetaH-expressing axons responded most and least vigorously, respectively. Serotonergic axons were identified by serotonin (5-HT) or serotonin transporter (SERT) immunohistochemistry. Interestingly, a large increase in 5-HT compared to SERT-positive axons density in both saline and sNgR-treated rats indicated that serotonergic axons both sprouted and increased their transmitter content in response to rhizotomy and sNgR treatment. Calcitonin gene-related peptide-positive axons were largely depleted ipsilaterally by rhizotomy, and sNgR increased axon density only in deeper contralateral laminae (III-V). GAP-43 immunohistochemistry revealed a small increase in axon density following dorsal rhizotomy that was further augmented by sNgR treatment. These results reveal a differential effect of myelin antagonism on distinct populations of spinally projecting axons.