Background: Recent studies have indicated that inflammatory pathways and hypothalamic-pituitary-adrenal (HPA) axis function may be responsible for the interaction between pain and depression. Methods: Animals were examined for depressive and painful behavior following exposure to chronic unpredictable mild stress (CUMS) and chronic corticosterone (CORT) treatment. Subsequently, serum cytokines, adrenocorticotropic hormone (ACTH) and CORT were measured by enzyme-linked immunosorbent assay (ELISA). mRNA expression of cytokines in the brain were measured by quantitative PCR (qPCR). Results: The present study found that both CUMS and chronic CORT treatment induced behavioral changes of depression comorbid hyperalgesia. Moreover, both the treatments increased levels of serum ACTH, CORT, and cytokines including tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL1 beta), interleukin 6 (IL6), and Caspase 1 (CASP1). Following CUMS, IL1 beta levels were found to be elevated in all examined regions, including the raphe nuclei, thalamus, hippocampus, prefrontal cortex, and pituitary. In the raphe nuclei particularly, CUMS elevated all examined cytokine levels. Chronic CORT treatment, however, produced IL1 beta elevation in the hippocampus and the pituitary, with showing elevated levels in all examined cytokines. Limitation: To clarify the causal relationship between behavioral changes and altered cytokine levels via either antidepressant treatment or blockage of pre-inflammatory cytokine production, further studies should be conducted. Conclusions: Despite similar behavioral consequences, hypercortisolism and peripheral inflammation, CUMS and chronic CORT treatment seem to produce differing inflammatory brain responses.