Many chronic pain conditions remain difficult to treat, presenting a high burden to society. Conditions such as complex regional pain syndrome may be maintained or exacerbated by sympathetic activity. The discovery of abnormal connections between sympathetic and sensory neurons, e.g. the sprouting of sympathetic fibers into the sensory ganglia (DRG) after peripheral nerve injury, offered a possible explanation, but studies of this effect yielded conflicting findings. New tools and knowledge are now available to overcome some limitations of previous work in this field, as proposed: 1) The contribution of sympathetic transmitters other than norepinephrine (NE) will be examined. Many previous studies relied solely on NE antagonists, ignoring known sympathetic co-transmitters such as ATP, which is particularly important in pathological conditions. New reagents for specific ATP receptor subtypes will help investigate its role. 2) Functional studies of the sympathetic-sensory neuron connection were very limited. The proposed research will use a described new preparation for stimulating the sympathetic fibers that have sprouted into the DRG while recording intracellularly many parameters of sensory neuron excitability. 3) The possible interaction of satellite glial cells and sympathetic sprouts has not been investigated. The importance of activated glia in pathological pain has been recognized only recently. Experiments will test possible mechanisms by which reverberating interactions between sprouting sympathetic fibers, sensory neurons, and satellite glia cells might play key roles in initiating the pathological pain state. 4) Sympathetic effects on sensory neurons may shift from early excitatory to later inhibitory ones, accounting for conflicting findings. This shift occurs in other model systems of chronic inflammation. The function of sympathetic sprouts at later time points will be examined. 5) The role of local inflammation in promoting sympathetic sprouting has not been fully recognized. Local DRG inflammation is sufficient to induce sprouting, and can enhance sprouting caused by axotomy. Functional mechanisms and behavioral relevance of sympathetic - sensory neuron interactions in pain models will be examined using 3 specific aims: SA1: To characterize functional effects of sympathetic fibers on DRG excitability, spontaneous activity and pain behavior, including determining the effects of a very limited form of surgical sympathectomy that eliminates sprouting in a single DRG. SA2: To determine whether sympathetic transmitters in addition to NE play important excitatory roles in abnormal sympathetic-sensory neuron interactions, focusing on possible roles of ATP and satellite glia cells. SA3: To determine the interactions between localized inflammation, sympathetic outgrowth and neuropathic pain. We will determine whether sympathetic spouts regulate inflammatory responses in the early phases of two pain models, as suggested by work in other models of chronic inflammation. The proposed experiments will reinvigorate the study of sympathetic-sensory interactions in chronic pain conditions, and help find new approaches to this serious clinical problem.

Public Health Relevance

Chronic pain conditions such as CRPS are common, long-lasting, and debilitating. We propose to continue the study of sympathetic component in neuropathic pain. Using a rat/mouse model, we will determine how abnormal activity, inflammation, ATP release affect sympathetic outgrowth and the neurons that sense pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045594-09
Application #
8443828
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Jakeman, Lyn B
Project Start
2003-02-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$324,789
Indirect Cost
$117,917
Name
University of Cincinnati
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ye, Ling; Xie, Wenrui; Strong, Judith A et al. (2014) Blocking the mineralocorticoid receptor improves effectiveness of steroid treatment for low back pain in rats. Anesthesiology 121:632-43
Strong, Judith A; Xie, Wenrui; Bataille, Feguens J et al. (2013) Preclinical studies of low back pain. Mol Pain 9:17
Xie, Wenrui; Strong, Judith A; Ye, Ling et al. (2013) Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia. Pain 154:1170-80
Xie, W; Strong, J A; Kim, D et al. (2012) Bursting activity in myelinated sensory neurons plays a key role in pain behavior induced by localized inflammation of the rat sensory ganglion. Neuroscience 206:212-23
Xie, Wenrui; Strong, Judith A; Kays, Joanne et al. (2012) Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion. Neurosci Lett 515:61-5
Dong, Fei; Du, Yi-Ru; Xie, Wenrui et al. (2012) Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC. Neurosci Bull 28:155-64
Du, Yi-Ru; Xiao, Yong; Lu, Zhuo-Min et al. (2011) Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways. Biochem Biophys Res Commun 408:32-7
Xie, Wenrui; Strong, Judith A; Mao, Juxian et al. (2011) Highly localized interactions between sensory neurons and sprouting sympathetic fibers observed in a transgenic tyrosine hydroxylase reporter mouse. Mol Pain 7:53
Li, Jing-Yi; Xie, Wenrui; Strong, Judith A et al. (2011) Mechanical hypersensitivity, sympathetic sprouting, and glial activation are attenuated by local injection of corticosteroid near the lumbar ganglion in a rat model of neuropathic pain. Reg Anesth Pain Med 36:56-62
Xie, Wenrui; Strong, Judith A; Zhang, Jun-Ming (2010) Increased excitability and spontaneous activity of rat sensory neurons following in vitro stimulation of sympathetic fiber sprouts in the isolated dorsal root ganglion. Pain 151:447-59

Showing the most recent 10 out of 26 publications