Depression and chronic pain frequently co-occur and are difficult to treat. In the first award period, we identified mechanisms common to both depression and pain as well as mechanisms specific to depression. We showed that inflammatory activity in the spinal cord is at the origin of both pain and depression in a mouse model of chronic neuropathic pain in response to nerve injury. However, depression additionally requires in- flammation-induced activation of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase (IDO1). In this renewal application, we propose to change our focus from the mechanisms underlying devel- opment of depression and chronic pain to the endogenous resolution mechanism that normally prevents transition to these maladaptive, long-lasting consequences of inflammation. We have obtained exciting new findings identifying a key role for CD8 T cells in the resolution of depression and pain. Our preliminary data indicate that T cells and endogenous peripheral monocytes that produce the cyto- kine interleukin (IL)-10 are required for resolution of inflammation-induced pain and depression. Mice that genetically lack T cells develop prolonged pain and depression in two different models of peripheral inflamma- tion. Adoptive transfer of T cells to these mice normalizes resolution of pain and depression without altering the course of peripheral inflammation. The prolonged depression in T cell-deficient mice versus control mice is associated with persistent elevation of IDO1 and lack of IL-10 production in the brain. Our overall hypothesis is that CD8 T cells promote resolution of depression and pain by inducing IL-10 production by monocytes/macrophages. This leads to the downregulation of glial activation in the central nerv- ous system. In addition, we propose that CD8 T cells that have been educated in vivo in either an antigen-spe- cific or a non?antigen-specific way will be more efficient than T cells from nave mice will be in promoting res- olution of inflammation-induced pain and depression. We will pursue 3 specific aims to test this set of hypotheses:
Aim 1 : Examine the role of T cells in the resolution of depression-like behavior and pain;
Aim 2 : Investigate the contribution, source, and target cell of endogenous IL-10 in promoting resolution of depression and pain;
Aim 3 : Assess whether T cells are educated in vivo to promote resolution of depression and pain. Our proposal is innovative because the concept that neuroimmune T cell-dependent mechanisms are re- quired for recovery from depression pain opens a totally novel perspective on the treatment of comorbid pain and depression. This project is significant because of the high prevalence of comorbid depression and chronic pain and the lack of effective treatment. If successful, our project will unravel unexplored endogenous path- ways governing resolution of depression and pain, and thereby allow the development of novel strategies for treatment, including ex vivo T cell education or vaccination strategies.

Public Health Relevance

The proposed research is relevant to public health because identification of the endogenous resolution pathways of depression and pain will lead to novel interventions to prevent these disorders in patients at risk because of inflammation. Thus the proposed research is relevant to the part of the mission of the National Institute of Neurological Diseases and Stroke (NINDS) and the National Institute of Mental Health of the National Institutes of Health that pertains to seeking fundamental understanding about the brain and using that knowledge to reduce the burden of neurological disease and mental illnesses.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
Zip Code
Walker, Adam K; Wing, Emily E; Banks, William A et al. (2018) Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol Psychiatry :
Ma, Jiacheng; Kavelaars, Annemieke; Dougherty, Patrick M et al. (2018) Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer 124:2289-2298
Laumet, Geoffroy; Edralin, Jules Daniel; Chiang, Angie Chi-An et al. (2018) Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling. Neuropsychopharmacology 43:2597-2605
Lacourt, Tamara E; Vichaya, Elisabeth G; Chiu, Gabriel S et al. (2018) The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci 12:78
Singhmar, Pooja; Huo, XiaoJiao; Li, Yan et al. (2018) Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy. Pain 159:884-893
Wang, Hui-Jing; Gu, Han-Xin; Eijkelkamp, Niels et al. (2018) Low GRK2 Underlies Hyperalgesic Priming by Glial Cell-Derived Neurotrophic Factor. Front Pharmacol 9:592
Dantzer, Robert (2018) Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev 98:477-504
Kappelmann, N; Lewis, G; Dantzer, R et al. (2018) Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 23:335-343
Colpo, Gabriela D; Leboyer, Marion; Dantzer, Robert et al. (2018) Immune-based strategies for mood disorders: facts and challenges. Expert Rev Neurother 18:139-152
Khandaker, G M; Dantzer, R; Jones, P B (2017) Immunopsychiatry: important facts. Psychol Med 47:2229-2237

Showing the most recent 10 out of 46 publications