The rat neurokinin-1 (NK1) receptor gene contains a cyclic adenosine monophosphate (cAMP) response element, and gene transcription may be activated upon binding of phosphorylated cAMP response element binding protein (pCREB). If pCREB contributes to increased expression of NK1 receptors, pCREB should increase in neurons that express NK1 receptors under conditions that increase NK1 receptor mRNA. Evidence for this relationship was found following injection of formalin into one hindpaw of rats. Immunohistochemistry was employed to visualize NK1 receptors and pCREB in spinal cord sections. Formalin injection produced an increase in pCREB-immunofluorescence within NK1 receptor-immunoreactive neurons from segments L4 and L5. No change occurred in pCREB-immunofluorescence within NK1 receptor-immunoreactive neurons from segment T11. These data support the hypothesis that transcription factor pCREB contributes to increased expression of spinal NK1 receptors during persistent pain.