Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling

Abstract

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: 1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and 2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1−/− mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1−/− mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.

Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors

“…Other chronic pain models in animals have also observed similar anxiety-like behavior after migraine-induced pain and sciatic nerve injury (Robinson et al, 1988, Lipton et al, 2000, McWilliams et al, 2003, McWilliams et al, 2004, Dellarole et al, 2014). Of further note is that mice with TIC injury develop the anxiety-like behaviors by week 8 post-injury in each of the three tests.…”

“…The “pain affect” has also been described as the squeal of other physical and psychological disorders such as anxiety and depression (McWilliams et al, 2003, McWilliams et al, 2004, Maletic and Raison, 2009, Dellarole et al, 2014). These comorbidities have been so prevalent that approximately half of all patients suffering from chronic pain are also described as suffered from anxiety and depression (Asmundson and Katz, 2009, Asmundson and Taylor, 2009, Robinson et al, 2009, Macianskyte et al, 2011).…”

The hippocampus and TNF: Common links between chronic pain and depression

“…Mice receiving sciatic nerve CCI to induce neuropathic pain developed depressive-like behavior 4 weeks following ligature placement that was associated with increased hippocampal TNF and impaired dentate gyrus neurogenesis dependent on TNF receptor-1 signaling (Dellarole et al, 2014). In addition to various harmful effects of cytokines on neurons, depression mediates the activation of resident brain macrophages including microglia, which contribute to the existing immune disruption by releasing more cytokines (Frank et al, 2007;Maletic et al, 2007).…”

Coexistence of Chronic Pain and Depression: A Short Review with a Focus on the Antidepressant Effect of Tramadol and Buprenorphine

“…They hypothesized that chronic neuropathic pain-induced depression might be dependent on hippocampal tumor necrosis factor (TNF) through TNF receptor 1 (TNFR1) and is associated with different forms of hippocampal changes such as reduced neurogenesis, neuronal plasticity, and myelin remodeling. Other neuroplastic changes such as reduced spine density and dendritic retraction, were also described in animal models of depression or pain [103]. Therefore, it can be stated, that neurodegeneration is the primary defect in the induction of depression and chronic pain cycle of intensification.…”

“…Dellarole et al [103] showed a temporal relationship between neuropathic pain and the occurrence of depressive-like symptoms as well as structural neuroplastic and white matter impairments of the hippocampus. They hypothesized that chronic neuropathic pain-induced depression might be dependent on hippocampal tumor necrosis factor (TNF) through TNF receptor 1 (TNFR1) and is associated with different forms of hippocampal changes such as reduced neurogenesis, neuronal plasticity, and myelin remodeling.…”