Pathological pain is associated with transcriptional alterations in key genes and induction of sustained neuronal plasticity (Ji & Woolf, 2001). The regulatory transcription factor, zif268 has been linked to plasticity underlying persistent cell modification and shown to be regulated by acute noxious stimulation (Nolan A 1987). The aim of this study was characterise the expression of zif268 in spinal cord in a clinical model of persistent inflammatory disease and hyperalgesia (Ley et al. 1989).Thresholds to noxious mechanical stimulation of each leg were measured in Newtons (Rahman et al. 2002) in adult female sheep affected by unilateral lameness, clinically diagnosed as footrot, a bacterial infection of the digital tissues, and 12 healthy-control sheep. After establishing baseline thresholds, 34 lame sheep were treated according to standard clinical practice (foot bathing, pairing of the horny tissue surrounding the infected area, antibiotics (tetracycline, 20 mg/kg, i.m.)). Following treatment, thresholds were measured at set intervals for up to 30 days. Spinal cord tissues were collected from lame animals humanely killed before treatment (n = 6) and 3 days after treatment (n = 6), and healthy-control sheep (n = 6). Spinal cords were sectioned mid-line and processed for zif268 mRNA and protein using real-time RT-PCR and Western blotting, respectively. Data presented are mean ± S.E.M. and were analysed using ANOVA with post-hoc Tukeys test. Mechanical thresholds were significantly reduced on the limb affected by lameness compared to healthy-control animals (12.8 ± 0.8 N and 18.7 ± 1 N, respectively; p < 0.001), and compared to all other limbs (17.6 ± 0.9 N; p < 0.001). Hyperalgesia was significantly attenuated 2 days after treatment and had completely resolved by day 3 (p < 0.01). Zif268 mRNA and protein were found to be constitutively expressed in control sheep spinal cord. Significant bilateral up-regulation of zif268 mRNA (3.5-fold increase ipsilaterally and contralaterally; p < 0.05) and zif268 protein (190 ± 19% ipsilaterally and 160 ± 6 % contralaterally of control levels; p < 0.05) was detected in spinal cord recovered from lame sheep displaying hyperalgesia. Three days after treatment zif268 mRNA and protein expression had returned to control values.These results demonstrate that zif268 is elevated in spinal cord in response to persistent inflammation and hyperalgesia. This suggests that zif268 activity and downstream targets may be the trigger for long-lasting neuronal plasticity thought to underlie altered behaviours associated with persistent inflammatory pain.