BACKGROUND: Tumor necrosis factor a (TNF-alpha) could trigger p38 mitogen-activated protein kinase (MAPK) activation. Conversely phosphorylated p38 (p-p38) could induce the upregulation of TNF-alpha. In this study, we examined the hypothesis that chronic constrictive injury (CCI) of the sciatic nerve could promote spinal cord release of TNF-a and produce allodynia via the p38 MAPK pathway. METHODS: Sprague-Dawley rats were divided into five groups: 1) naive control rats, 2) sham surgery rats, 3) CCI surgery rats without treatment, 4) CCI surgery rats inhibitor with saline (0.9%) treatment, and 5) CCI surgery rats with the p38 MAPK inhibitor SB203580 treatment. In treatment groups, saline or SB203580 (2 mu g, twice a day) was given intrathecally starting I day before or I day or 7 days after CCI. All rats were killed at different times after surgery to examine p38 MAPK activity and TNF-a levels in the spinal cord by Western blot analysis or immunohistochemistry. Mechanical allodynia was tested by a series of von Frey hairs 3, 7, and 14 days after surgery. RESULTS: p-p38 MAPK was significantly increased at 3, 7, and 14 days after CCI surgery compared with time-matched shams (P < 0.05). Peripheral nerve injury induced mechanical allodynia and enhanced spinal concentrations of TNF-alpha (P < 0.05). Pretreatment or early treatment with SB203580 inhibited p38 MAPK activity, resulting in reduction of TNF-a synthesis and attenuation of mechanical allodynia (P < 0.05). CONCLUSION: p38 MAPK activation is one aspect of the signaling cascade that culminates in TNF-a synthesis and contributes to mechanical allodynia after peripheral nerve injury.