Clinically, many chronic pain conditions are worsened by or even dependent upon activity of the sympathetic nervous system. Sympathetic blockade is often used clinically in chronic pain conditions, but the clinical and preclinical evidence for thi practice has been contradictory and incomplete. However, a very recent study showed dramatic and promising results using a catheter approach to provide longer lasting sympathetic blockade than is achieved by injection, in patients with intractable pain. Most preclinical research has focused on the abnormal interactions between the sensory and sympathetic nervous systems in models of chronic pain. Based on our preliminary data and recent publications, we propose that the initiation and persistence of certain pathological pain conditions requires intact sympathetic innervation of the sensory nervous system at the level of the sensory ganglion, and that release of sympathetic transmitters enhances local inflammation of the sensory ganglia and leads to pain. Local inflammatory responses in the sensory ganglia occur even after remote nerve injuries, so this phenomenon is important to understanding many types of chronic pain conditions. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a microsympathectomy (mSYMPX) in both neuropathic and inflammatory pain models. This procedure involves cutting the gray rami (sympathetic postganglionic fibers) to only the lumbar sensory ganglia. mSYMPX avoids many effects of chemical or surgical sympathectomy used in most previous studies, such as sympathetic denervation of primary and secondary immune tissues. Since sympathetic innervation of some of these tissues is anti-inflammatory, global sympathectomy may have obscured pro-inflammatory effects at the sensory ganglion level. The mSYMPX method is also more clinically relevant since patients often receive local sympathetic blocks. The hypothesis will be tested in 3 specific aims: 1) To characterize the effects of mSYMPX on the development and persistence of pain and on local inflammation in the DRG. The effects of mSYMPX after pain is well-established will be tested, and its effects on infiltration of immune cells in the sensory ganglia examined with microscopy. 2) To explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG. Effects of mSYMPX on local cytokine levels and immune cell polarization will be examined, based on our preliminary finding that the pro-inflammatory cytokines induced by a pain model are normalized by mSYMPX. 3) To assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG. Using novel methods developed in our laboratory for locally perfusing the sensory ganglia and locally knocking down specific molecules, we will examine the roles of different noradrenergic and ATP receptors in mediating the pro-inflammatory role of the sympathetic fibers. The proposed experiments will elucidate a novel mechanism for sympathetically maintained pain with relevance to several chronic pain conditions with inflammatory component.

Public Health Relevance

Chronic pain conditions such as complex regional pain syndrome (CRPS) are common, long-lasting, and debilitating. We propose to continue the study of the sympathetic component of pathological pain by testing a novel mechanism of action. Specifically, using rat models, we will determine how sympathetic innervation of the dorsal root ganglia contributes to the development and persistence of pathological pain by regulating local immune/inflammatory responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045594-12
Application #
9208801
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Jakeman, Lyn B
Project Start
2005-05-04
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
12
Fiscal Year
2017
Total Cost
$349,889
Indirect Cost
$128,440
Name
University of Cincinnati
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J et al. (2017) FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Arch 469:195-212
Li, Ai-Ling; Zhang, Jing-Dong; Xie, Wenrui et al. (2017) Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models. Neurosci Bull :
Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy et al. (2016) Upregulation of the sodium channel NaV?4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation. Pain 157:879-91
Xie, Wenrui; Chen, Sisi; Strong, Judith A et al. (2016) Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain. J Neurosci 36:8712-25
Ibrahim, Shaimaa I A; Strong, Judith A; Zhang, Jun-Ming (2016) Mineralocorticoid Receptor, A Promising Target for Improving Management of Low Back Pain by Epidural Steroid Injections. J Anesth Perioper Med 3:177-184
Chen, S; Xie, W; Strong, J A et al. (2016) Sciatic endometriosis induces mechanical hypersensitivity, segmental nerve damage, and robust local inflammation in rats. Eur J Pain 20:1044-57
Chen, Si-Si; Zhang, Jun-Ming (2015) Progress in Sympathetically Mediated Pathological Pain. J Anesth Perioper Med 2:216-225
Barbosa, Cindy; Tan, Zhi-Yong; Wang, Ruizhong et al. (2015) Nav?4 regulates fast resurgent sodium currents and excitability in sensory neurons. Mol Pain 11:60

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