TNF in the hippocampus: Changes in the levels of this cytokine regulate symptoms of chronic pain and depression

An increased level of the cytokine tumor necrosis factor alpha (TNFalpha) has been shown to be involved in the manifestation of both chronic pain and depression with respect to the hippocampus. Previous studies in this lab have shown that this area of the brain plays a fundamental role in mechanisms involved in nociception. Likewise, studies in this lab have also demonstrated that when TNF activity is blocked by intracerebroventricular (icv) infusion of a TNF antibody adjacent to this area of the brain there is a decrease in TNF activity and alleviation of pain and depressive-like behaviors. Therefore, this indicates that TNF is not a consequence of pain/depression, but can actually induce these behaviors/symptoms. To verify this, icv infusion of recombinant TNF adjacent to the hippocampus induced depressive-like behaviors, as well as pain behavior similar to that expressed during a model of chronic, neuropathic pain. These findings led to the hypothesis for this thesis project, that increased production of TNF specifically in the hippocampus leads to induction of pain behaviors and decreased production of TNF in this region alleviates depressive-like behavior. As an extension of previous studies, in the present study, levels of TNF in the hippocampus were directly regulated and the effect on depressive-like and pain behaviors were assessed. Male, Sprague-Dawley rats received intraperitoneal (i.p.) antidepressant injections, stereotaxic microinjection of gold nanorod (GNR) complexed-TNF siRNA to knock-down TNF production, or microinjection of GNR-complexed plasmids to increase the amount of TNF secreted in the hippocampus. Pain responses are measured using thermal hyperalgesia and mechanical allodynia on rats microinjected with GNR-TNF plasmid complexes; depressive responses are measured using the novel induced-hypophagia (NIH) test on rats administered an antidepressant drug chronically or receiving a bilateral intra-hippocampal microinjection of GNR-TNF-siRNA. As a result of collaboration with other labs, we have found that similar to chronic antidepressant drug administration, depressive-like behavior in the NIH test is alleviated by rats receiving intra-hippocampal microinjection of GNR-TNF siRNA. Supporting this behavioral finding is the significant decrease in immunoreactive staining for TNF in this brain region. In animals receiving hippocampal microinjection of GNR-TNF plasmid complexes, thermal hyperalgesia developed that was significant from control plasmid injected animals. In support of this behavioral finding, immunoreactive staining for TNF, bioactive levels of TNF, and levels of TNF mRNA as per PCR analysis were increased in this brain region. Therefore, these findings strongly support the conclusion that enhanced levels of TNF in the hippocampus are not a consequence of pain/depression, but induce these behaviors/symptoms.