Comorbidity of chronic pain and depression: The hippocampus as a common denominator
Fasick, Victoria R.
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Patients who suffer from chronic pain are often afflicted with depressive illness as well, and vice versa. Antidepressants are common forms of treatment for both chronic pain and depression, but a definitive mechanism of action is still unknown. The hippocampus has been well accepted as a brain region involved in depressive illness and therapeutic action of antidepressant drugs, but it has yet to be accepted as a region that participates in pain processing. However, the pathogenesis of these two disease states share common neuromodulators and neurotransmitters acting within the hippocampus. Whereas the physiological and molecular basis for the coexistence of pain and depression is still being investigated, it is apparent that the hippocampus provides a viable anatomic link for these pathological disease states. Chronic pain and depressive illness can act as chronic inescapable stressors. Each of these disorders has been shown to produce neuroplastic changes, i.e., atrophy, of the hippocampus, one of the primary regions regulating affect within the limbic system. Specifically, both disorders affect the hypothalamic-pituitary-adrenal (HPA) axis, causing an elevation in glucocorticoid (GCC) levels accompanied by a decrease in GCC responsiveness, which in turn damages brain structures involved in the regulation of the HPA axis, most notably the hippocampus. Elevations in pro-inflammatory cytokines are routinely found in patients suffering from depression and chronic pain. GCCs are potent endogenous anti-inflammatory hormones; therefore, the reduced responsiveness that occurs during chronic pain and depressive illness causes a loss of GCC-mediated suppression of pro-inflammatory cytokine production. Pro-inflammatory cytokines also contribute to the increased production of the GCC. Thus, a vicious cycle is created, which results in elevated levels of cytokines and GCC. These cytokines also play a role in the turnover of monoamines within the hippocampus. For example, TNF-α inhibits the release of norepinephrine (NE), contributing to the overall insufficiency of NE that is commonly seen in depressive illness and chronic neuropathic pain. Administration of tricyclic antidepressants, agents that increase the availability of monoamines and regulate the production of cytokines, can be effective treatments for both depression and chronic pain. Likewise, the increase in hippocampal neurogenesis that occurs following antidepressant drug administration also lends support that the hippocampus is a common brain region important in mediating analgesic and antidepressant effects. The present review and investigation into the co-morbidity of depression and chronic pain will provide evidence that the hippocampus is a fundamental brain region involved in the development and maintenance of both disorders. The hypothesis that treatment and modification within the hippocampus would be advantageous to management of symptoms of chronic pain and major depressive disorders will be addressed.