Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to
55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of
its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients’ quality of
life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the
dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate. Recent studies have
demonstrated their critical roles in the development and maintenance of chronic pain. In this review, we summarized
the roles and mechanisms of PI3K/Akt pathway in the progression of chronic pain through sciatic nerve
injury, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia.