Substance P receptors were examined in crude synaptosomal fraction preparations of the rat spinal cord using [125I]Bolton Hunter Substance P ([125I]BHSP) which binds with an affinity of 0.043 +/- 0.015 nM. The concentration of binding sites in the dorsal and in the ventral part was 4.55 +/- 0.86 and 2.35 +/- 0.35 fmol mg-1, respectively. GTP inhibited the specific binding of [125I]BHSP in a concentration dependent manner, with 10(-3) mol l-1 GTP yielding 89-90% inhibition and 10(-5) mol l-1 GTP producing 50% inhibition. This value was similar in dorsal and ventral spinal cord. The effects on SP receptors of chronic treatment with the tricyclic antidepressant imipramine (2 x 10 mumol kg-1 day-1 p.o. 14 days) and the specific 5-HT (serotonin) uptake blockers alaproclate (2 x 20 mumol kg-1 day-1 p.o. 14 days) and zimelidine (2 x 10 mumol kg-1 day-1 p.o. 14 days) were examined in the ventral spinal cord, where SP and 5-HT coexist in the terminals of descending neurons from the raphe nucleus. Zimelidine treatment was found to cause a significant reduction in the number of substance P binding sites in the rat ventral spinal cord as compared to saline treated controls. These findings are discussed in light of the previous observation (Brodin et al. 1984) that SP levels are significantly elevated after treatment with antidepressant drugs especially with zimelidine, which alters the firing rates of 5-HT and 5-HT/SP neurons.