The present application aims at using neuroimmune approaches to understand the neurobiological basis of behavior. The objective is to study how deregulated interactions between the nervous and immune systems contribute to co morbidity of depression and pain. Depressive disorders and chronic pain represent two major health burdens in the Western world. Chronic pain predisposes to depression and vice versa, and 30-60% of the cases suffer from both depression and chronic pain. The broad question we seek to answer using a neuroimmune approach is: Why is chronic pain a risk factor for depression, and vice versa? Peripheral inflammation causes sickness behavior that can culminate into depressive behavior when the tryptophan metabolizing enzyme 2,3 indoleamine dioxygenase (IDO) is up regulated. We recently made the exciting discovery that an intracellular protein known as G protein coupled receptor kinase 2 (GRK2) possesses anti-inflammatory properties and acts as a molecular switch that regulates transition from acute to chronic pain. Our newest preliminary data indicate that low GRK2 enhances IDO expression by microglia in vitro. This proposal will test the completely novel concept that GRK2 is a critical molecule that explains the shared risk for developing depression and chronic pain. We have shown that chronic neuropathic pain or inflammation significantly reduces GRK2 in microglia from rodents. This finding is clinically important because low GRK2 in microglia is sufficient to transform transient inflammatory pain into chronic pain. We also showed that low GRK2 augments pro-inflammatory cytokine production and increases activation of p38 in vivo and in vitro. Moreover, we have preliminary data that p38 activity regulates IDO expression, which is key to development of inflammation-associated depressive-like behavior. We hypothesize that the reduction in microglial GRK2 caused by chronic neuropathic pain increases microglial p38 activity, pro-inflammatory cytokine production and IDO expression, thereby acting as risk factor for prolonged depressive-like and pain behaviors. To test this hypothesis, we will answer the following specific questions: 1. Is development of neuropathic pain and depressive-like behavior temporally related to the inflammation-induced reduction in GRK2 and the increase in IDO in CNS microglia/mf? 2. Is low GRK2 a risk factor for development of depressive-like behaviors and what is the mechanism? We will use mice with low GRK2 in microglia that we have generated using Cre-Lox technology. 3. Are comorbid depression and chronic pain both prevented by treatments that interfere with the loop of reduced GRK2, increase in p38 activity and upregulation of IDO? Collectively, these innovative experiments will identify low GRK2 as a completely novel risk factor for development of comorbid depression and chronic pain via a p38/cytokine/IDO-dependent pathway. Identification of these new molecular mechanisms underlying comorbid depression and pain is needed for effective development of novel prevention and therapeutic strategies.

Public Health Relevance

The proposed research is relevant and significant for public health because we anticipate discovering a novel shared neuroimmune risk factor for chronic pain and depression associated with nerve injury. The key is an enzyme known as G protein coupled receptor kinase-2. Delineation of neuroimmune pathways that mediate the effect of low GRK2 as a major risk factor in depression and pain is ultimately expected to enable development of novel therapeutic strategies aimed at treating the cause of these frequently co-occurring disorders. The proposed research is likely to have a major impact on the mission of the National Institute of Neurological Disorders and Stroke that is to reduce the burden of neurological disorders, including chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073939-05
Application #
8670785
Study Section
Special Emphasis Panel (ZRG1-IFCN-M (02))
Program Officer
Babcock, Debra J
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$421,353
Indirect Cost
$113,847
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Khandaker, G M; Dantzer, R; Jones, P B (2017) Immunopsychiatry: important facts. Psychol Med 47:2229-2237
Dantzer, Robert (2017) Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Curr Top Behav Neurosci 31:117-138
Laumet, Geoffroy; Zhou, Wenjun; Dantzer, Robert et al. (2017) Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. Brain Behav Immun 66:94-102
Brooks, Alexandra K; Lawson, Marcus A; Smith, Robin A et al. (2016) Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus. J Neuroinflammation 13:98
Baameur, Faiza; Singhmar, Pooja; Zhou, Yong et al. (2016) Epac1 interacts with importin ?1 and controls neurite outgrowth independently of cAMP and Rap1. Sci Rep 6:36370
Khandaker, Golam M; Dantzer, Robert (2016) Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl) 233:1559-73
Gonzalez-Pena, Dianelys; Nixon, Scott E; Southey, Bruce R et al. (2016) Differential Transcriptome Networks between IDO1-Knockout and Wild-Type Mice in Brain Microglia and Macrophages. PLoS One 11:e0157727
Krukowski, Karen; Eijkelkamp, Niels; Laumet, Geoffroy et al. (2016) CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain. J Neurosci 36:11074-11083
LaVoy, Emily C P; Fagundes, Christopher P; Dantzer, Robert (2016) Exercise, inflammation, and fatigue in cancer survivors. Exerc Immunol Rev 22:82-93
Gonzalez-Pena, Dianelys; Nixon, Scott E; O'Connor, Jason C et al. (2016) Microglia Transcriptome Changes in a Model of Depressive Behavior after Immune Challenge. PLoS One 11:e0150858

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