The intrathecal administration of p38 MAP kinase (p38) inhibitor has been shown to reduce hyperalgesia. In the present study, we investigated the activation of p38 in the rat dorsal root ganglion (DRG) and spinal cord following peripheral tissue inflammation and nerve injury immunohistochemically. Peripheral inflammation and chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the percentage of phosphorylated (P-) p38-immunoreactive (IR) neurons, primarily small sized ones in bilateral DRGs. In contrast, following axotomy, a significant decrease in the percentage of IR neurons was observed in ipsilateral DRGs. In addition, a marked increase was observed in the number of P-p38-IR microglia in the ipsilateral laminae I-IV and IX of the spinal cord following peripheral inflammation, CCI or axotomy. These findings suggest that p38 may play an important role in hyperalgesia and the activation of the spinal microglia.