THIS study demonstrated that hyperalgesia resulting from an intraneural injection of the cytokine tumor necrosis factor-alpha (TNF) was prevented by preemptive administration of a single dose of the prosaptide TX14(A) (200 μg/kg). TX14(A) is a synthetic 14-merpeptide with neurotrophic and cytoprotective activities. Efforts to elucidate TX14(A) antagonism of hyperalgesia concentrated on determining the effect of TX14(A) on the up-regulation of the 5 5 kDa TNF receptor (TNFR1) at the nerve injury site. It has been previously shown that TNFR1 expression is upregulated following nerve injury and parallels the display of nociceptive behavior. In our experiments, TNFR1 was decreased at the TNF nerve injection site in TX14(A)-treated rats when compared to vehicle-treated or control peptide-treated rats. Light microscopic evaluation of nerve injury site tissue displayed qualitatively similar neuropathology in both treatment groups during the time of peak hyperalgesia (day 3), but appeared more normal than untreated nerves at day 7 (histological scoring, mean ± s.d., 3.7 ± 0.57 for TX14(A)-treated and 5.67 ± 0.5 for control peptide-treated). These results suggest that TX14(A) decreased nociceptive behavior by attenuating both TNFR1 upregulation and Schwann cell activation in response to TNF injection. This prosaptide neurotrophin may also moderate nerve degeneration or promote regeneration. It is not known whether TX14(A) also acts rostral to the lesion site