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Chronic pain and depressive illness are debilitating disease states that are variably resistant to currently available therapeutic agents. Animal models of chronic pain are associated with activation of the hypothalamo-pituitary-adrenal (HPA) axis, upon which chronic pain acts as an inescapable stressor. Inescapable stress is also associated with [depressive-like] symptoms in experimental animals. Based on reports of the comorbidity between chronic pain and depressive illness in human patients, it is possible that these disease states are linked, via chronic stress-induced HPA dysfunction. Here, we discuss the possible involvement of the HPA axis in the aetiology of both chronic pain and clinical depression, and suggest a strategy for the development of novel pharmacotherapies.