Background Prostaglandin E(2) is an important spinal modulator of nociception. However, the effects of chronic opioid administration and withdrawal on prostaglandin E(2) release and associated signaling pathways in the spinal cord are generally unknown. Methods This study sought to examine these effects using a spinal microdialysis technique in a model of chronic morphine administration and withdrawal in the rat. Results The authors found that spinal prostaglandin E(2) release was unaffected by chronic morphine treatment but was significantly increased during withdrawal. Recurrent withdrawal did not further enhance this release. The authors also found up-regulation of cyclooxygenase-2 expression and phosphorylation of protein kinase Akt at Ser-473 in response to opioid withdrawal. In addition, they demonstrated that beta-catenin, a transcription factor downstream of Akt, was induced during morphine withdrawal, particularly during recurrent withdrawal. Conclusions These results suggest that opioid withdrawal activates signaling pathways associated with neuronal survival and transcriptional control, two processes implicated in neuronal development and synaptic plasticity.