There has been increasing awareness of neuroimmune interactions and their role in the etiology of diseases including stroke, Parkinson's disease, and chronic pain. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are unknown. We propose to employ a rat model of hind paw inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain. Recent studies indicate that pain processing can be vigorously facilitated by brainstem descending circuitry, a process that contributes to the development of chronic pain conditions. Abnormal pains after injury are linked to an enhanced neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. The emerging literature strongly implicates a role for glia and inflammatory cytokines in the development of hyperalgesia. Through still unknown mechanisms, glia can be activated after injury and release chemical mediators that modulate neuronal activity. Such glial-cytokine-neuronal interactions may be critical in the chronic pain process. To date, no studies have addressed the involvement of glia and related chemicals in descending facilitation of persistent pain. We propose to identify the cellular and molecular mechanisms of descending pain facilitation after tissue injury with an emphasis on neuronal-glial interactions in the RVM circuitry. We posit that 1) peripheral inflammation induces neuronal plasticity in the RVM circuitry involving activation of glia;and 2) RVM glial activation and inflammatory cytokine release facilitate neuronal plasticity through interactions with neuronal N-methyl-D-aspartate receptors (NMDAR) and contribute to the descending facilitation of hyperalgesia.
Aim 1 will test the hypothesis that glial cells are activated in the RVM after inflammation and affect neuronal function through release of inflammatory cytokine IL-12. Complete Freund's adjuvant will be injected into the hind paw to produce inflammation and behavioral hyperalgesia.
Aim 2 will determine whether neuron-to-glia signaling plays a role in glial activation after inflammation.
Aim 3 will test the hypothesis that astroglial activation in the RVM and associated IL-12 release facilitate neuronal plasticity through interaction with neuronal NMDAR and play a critical role in the development of hyperalgesia. Thus, we have proposed a model of reciprocal neuronal-glial interactions in the descending facilitation of persistent pain. Advancing from previous studies, the model emphasizes activation of glia by injury-generated neuronal input, concomitant cytokine release, and post-translational regulation of NMDAR through IL-12 signaling. The outcome of these studies will enhance understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain. Public Health Significance: We propose to employ a rat model of inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain conditions. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are largely unknown. The outcome of these studies will enhance understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060735-02
Application #
7618658
Study Section
Special Emphasis Panel (ZRG1-CFS-E (01))
Program Officer
Porter, Linda L
Project Start
2008-05-01
Project End
2013-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$328,125
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Ren, Ke; Dubner, Ronald (2016) Activity-triggered tetrapartite neuron-glial interactions following peripheral injury. Curr Opin Pharmacol 26:16-25
Bai, Guang; Ren, Ke; Dubner, Ronald (2015) Epigenetic regulation of persistent pain. Transl Res 165:177-99
Guo, Wei; Imai, Satoshi; Dubner, Ronald et al. (2014) Multipotent stromal cells for arthritic joint pain therapy and beyond. Pain Manag 4:153-62
Guo, Wei; Miyoshi, Kan; Dubner, Ronald et al. (2014) Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade. Mol Pain 10:35
Zhang, R-X; Ren, K; Dubner, R (2013) Osteoarthritis pain mechanisms: basic studies in animal models. Osteoarthritis Cartilage 21:1308-15
Meng, Xianze; Zhang, Yu; Lao, Lixing et al. (2013) Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model. Pain 154:294-305
Ren, Ke (2012) Further evidence on a role of chemokines in injury-related pain hypersensitivity: commentary on a paper by Saika et al. (2012, this issue). Eur J Pain 16:1209-10
Guo, Wei; Wang, Hu; Zou, Shiping et al. (2012) Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation. Neurosci Bull 28:193-207
Guo, Wei; Wang, Hu; Zou, Shiping et al. (2011) Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells 29:1294-303
Gu, Ming; Miyoshi, Kan; Dubner, Ronald et al. (2011) Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade. J Neurosci 31:12823-36

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