More than 30 million Americans suffer from unrelieved chronic pain, which is regarded as a disease with its own pathology. Current studies focus on how pain is induced, but it is unclear how acute pain naturally resolves. We hypothesize that disruption of local active pro-resolving processing will result in chronic pain. Our recent studies have shown that the pro-resolution lipid mediators (PRLMs) such as resolvins and protectins, derived from omega-3 unsaturated fatty acids DHA and EPA, are potent inhibitors of inflammatory and neuropathic pain. Mechanistically, PRLMs not only normalize synaptic plasticity but also suppress glial activation in the spinal cord. Resolvins are also potent endogenous inhibitors of TRPA1 or TRPV1 (IC50=1-10 nM). However, the signaling mechanisms of PRLMs are elusive. b-arrestin-2 (barr2) is a scaffold protein that is classically involved in desensitization of GPCRs. However, the unique role of barr2 in regulating NMDA receptor function and inflammatory/neuropathic pain is unknown. The overall goal of this application is to investigate how barr2 arrests pain and whether PRLMs resolve pain via barr2. Our central hypothesis is barr2, activated by some PRLMs, arrests pain and contributes to the resolution of inflammatory and neuropathic pain via masking ERK activation. We will test this hypothesis via the following specific aims:
Aim 1, to establish that barr2 is essential for the resolution of inflammatory and neuropathic pain, and Aim 2, to define the peripheral and central roles of PRLMs and barr2 in pain resolution, by modulating TRPA1/V1 function in DRG neurons, NMDAR function in spinal cord neurons, and ERK activation in neurons and glia. We believe this proposal is highly significant by testing a novel pain resolution pathway mediated by PRLMs or/and barr2. Our approach is multidisciplinary that combines genetic manipulation (transgenic mice, conditional knockout mice, gene therapy), electrophysiology, and behavioral testing for evoked pain and spontaneous pain (CPP). We will also test the role of PRLMs in human DRG neurons to increase the translational potential. The proposed study will not only identify a pro- resolution pathway for pain arrest but may also lead to the development of novel pain therapeutics.

Public Health Relevance

Current studies focus on how pain is induced, but the resolution mechanisms and pathway of pain remains unknown. The overall goal of this application is to investigate how the pro- resolution lipid mediators such as resolvins and protectin contribute to the resolution of inflammatory and neuropathic pain via the activation of the scaffold protein b-arrestin-2. To this end, we will employ a multidisciplinary approach that combines genetic manipulation (transgenic mice, siRNA knockdown, and gene therapy), behavioral tests for evoked and ongoing pain, and electrophysiology. This study will identify a novel pro-resolution pathway for 'pain arrest' and lead to the development of new pain therapeutics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Chang, Wonseok; Berta, Temugin; Kim, Yong Ho et al. (2018) Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences, and Regulation by Paclitaxel. Neurosci Bull 34:4-12
Luo, Xin; Fitzsimmons, Bethany; Mohan, Apoorva et al. (2018) Intrathecal administration of antisense oligonucleotide against p38? but not p38? MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice. Brain Behav Immun 72:34-44
Xie, Rou-Gang; Gao, Yong-Jing; Park, Chul-Kyu et al. (2018) Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms. Neurosci Bull 34:13-21
Ji, Ru-Rong; Nackley, Andrea; Huh, Yul et al. (2018) Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 129:343-366
Chen, Gang; Zhang, Yu-Qiu; Qadri, Yawar J et al. (2018) Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain. Neuron 100:1292-1311
Zhang, Linlin; Terrando, Niccolò; Xu, Zhen-Zhong et al. (2018) Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. Front Pharmacol 9:412
Chamessian, Alexander; Young, Michael; Qadri, Yawar et al. (2018) Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn. Sci Rep 8:6809
Han, Qingjian; Liu, Di; Convertino, Marino et al. (2018) miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus. Neuron 99:449-463.e6
Bang, Sangsu; Xie, Ya-Kai; Zhang, Zhi-Jun et al. (2018) GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J Clin Invest 128:3568-3582
Berta, Temugin; Qadri, Yawar; Tan, Ping-Heng et al. (2017) Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain. Expert Opin Ther Targets 21:695-703

Showing the most recent 10 out of 23 publications