Neuropathic pain in somatic and orofacial regions is difficult to treat, in part due to our incomplete understanding of cellular and molecular mechanisms underlying the genesis of neuropathic pain. Our work performed in the previous term of this grant has demonstrated how spinal cord microglial cells interact with neurons after nerve injury to drive neuropathic pain. We have demonstrated that activity-dependent activation of p38 MAPK in spinal cord microglia serves as a critical signaling for the genesis of neuropathic pain by producing the proinflammatory cytokines TNF-a and IL-1b. We have also demonstrated that TNF-a and IL-1b can powerfully regulate synaptic transmission in the spinal cord. However, mechanisms of neuronal-glial interactions after nerve injury are not fully understood. Recent studies show that caspases not only induce neuronal degeneration but also regulate synaptic plasticity. Our pilot studies have shown that (1) nerve injury up-regulates caspase-6 in spinal cord axonal terminals and (2) caspase-6 induces a substantial release of TNF-a in microglia. The overall goal of this competing renewal is to investigate how caspase-6 drives neuropathic pain via neuronal-glial interactions. We will test the following hypotheses via 4 specific aims using a mouse spinal nerve ligation model of neuropathic pain.
Aim 1. Test the hypothesis that caspase-6 is both sufficient and required for the genesis of neuropathic pain and activation of spinal cord microglia;
Aim 2. Test the hypothesis that nerve injury results in caspase-6 up-regulation in primary sensory neurons and spinal cord axons and induces caspase-6 release from primary sensory neurons;
Aim 3. Test the hypothesis that caspase- 6 induces neuropathic pain by releasing TNF-a from microglia;
and Aim 4. Test the hypothesis that caspase-6 rapidly enhances synaptic transmission and induces neuroplasticity in the spinal cord dorsal horn via TNF- a and microglial signaling. The proposed studies will use a multidisciplinary approach, including behavioral testing, siRNA knockdown, microglial culture, patch clamp recording in spinal cord slices and LTP recordings in intact animals, and caspase-6 and TNFR knockout mice to investigate caspase-6-induced neuronal-glial interactions after nerve injury. These studies will not only provide further insights into nerve injury-induced neuronal-glial interactions, but may also identify caspase-6 as a new target for treating neuropathic pain in the somatic and orofacial regions.

Public Health Relevance

Activation of microglial cells in the spinal cord after nerve injury contributes to the development of neuropathic pain via neuronal-glial interactions. We will employ multidisciplinary approaches such as behavioral, biochemical, and electrophysiological approaches to define caspase-6-induced neuronal-glial interactions in a nerve injury-induced neuropathic pain condition. Given the incomplete understanding of neuropathic pain mechanisms and insufficient treatment of neuropathic pain, this application will provide new insights into neuronal-glial interactions in neuropathic pain and identify novel target for neuropathic pain management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017794-10
Application #
8640766
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
2006-07-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Chen, Gang; Luo, Xin; Qadri, M Yawar et al. (2018) Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes. Neurosci Bull 34:98-108
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
Ji, Ru-Rong (2018) Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue. Neurosci Bull 34:1-3
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

Showing the most recent 10 out of 88 publications