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Brain Behav Immun. 2014 Oct;41:65-81. doi: 10.1016/j.bbi.2014.04.003. Epub 2014 Jun 2.

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

Author information

1
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
2
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil.
3
Laboratory of Neuroplasticity and Pain, Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
4
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States; The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Department of Biology, Drexel University, Philadelphia, PA 19104, United States. Electronic address: jrb445@drexel.edu.

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.

KEYWORDS:

Cytokines; Depression; Myelin; Neurogenesis; Neuropathic pain; Plasticity; TNF; TNFR1

PMID:
24938671
PMCID:
PMC4167189
DOI:
10.1016/j.bbi.2014.04.003
[Indexed for MEDLINE]
Free PMC Article

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