Approximately 6% of the American population suffers from intractable pain following nerve injury;yet available treatment options are only marginally effective. Persistent pain was previously attributed exclusively to sensory neuron functions;however, recent discoveries indicate that glial cells also contribute to chronic pain. Activation of satellite glial cells (SGCs), the type of glial cell surrounding primary sensory neurons, correlates with increased sensory neuron excitability. A better understanding of this glia-induced hyper-excitability is likely to open the door to new therapies for nerve-injured patients. Until recently, means of studying the role of glial cells in nerve injury were limited. By using stereotactically targeted RNA interference (RNAi) to inhibit gene expression, we can now silence specific genes in single sensory ganglia of adult rats. Here, we have chosen to study a series of SGC-specific genes involved in neuronal excitability including genes that code for a neurotransmitter receptor (P2Y4), an enzyme (guanylyl cyclase), a calcium-activated potassium channel (SK3), and a component of the gap junction (connexin 43). These genes are likely to play key roles in neuropathic pain since they regulate neuron-SGC communication and control neuronal excitability following injury. Our preliminary experiments utilizing RNAi-mediated gene silencing at the trigeminal ganglion, where SGCs surround the cell bodies of primary sensory neurons innervating the face, show that this approach selectively and reversibly silences SGC genes in freely behaving rats. We can quantify the effects of gene silencing in these animals through several behavioral tests, as well as by anatomical and physiological analyses. This proposal aims to elucidate the contribution of SGC-specific genes to the control of neuronal excitability and sensory behavior following trigeminal nerve injury. With these results we hope to define genetic targets for the development of therapies that could improve the lives of individuals suffering from the long-term effects of nerve injury. The Principal Investigator of this proposed study directs, and serves as the neurosurgeon for, the Interdepartmental Pain Group at Cedars-Sinai Medical Center and is a member of the Cedars-Sinai Gene Therapeutics Research Institute, where this work will be completed. Fifty percent of the Principle Investigator's time is protected to pursue research.

Public Health Relevance

Approximately 6% of the American population suffers from intractable pain following nerve injury;yet available treatment options are only marginally effective. Persistent pain was previously attributed exclusively to sensory neuron functions;however, recent discoveries indicate that glial cells also contribute to chronic pain. Activation of satellite glial cells (SGCs), the type of glial cell surrounding primary sensory neurons, correlates with increased sensory neuron excitability. A better understanding of this glia-induced hyper-excitability is likely to open the door to new therapies for nerve-injured patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061241-05
Application #
8197031
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Porter, Linda L
Project Start
2008-06-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$447,125
Indirect Cost
$157,724
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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