Pain, one of the oldest medical problems still remains an immense clinical challenge. Our ability to effectively treat acute and especially chronic painful conditions often causes other unwanted side-effects that degrade the quality of life. TRPV1, also known as the capsaicin receptor, has been at the forefront of research focused on the development of new strategies to treat chronic painful conditions that arise from inflammation. TRPV1 is expressed in primary afferent nociceptors (specialized sensory neurons) that detect painful stimuli and its expression is increased in these nerve cells under conditions of inflammation. Increased levels of TRPV1 appear to drive the development of persistent pain and hyperalgesia. Surprisingly, little is known about what controls the production of TRPV1 in the nervous system under normal or inflammatory conditions. The current project is focused on: 1) Understanding how inflammatory mediators released at the site of injury, such as Nerve Growth Factor (NGF), increase TRPV1 production under conditions of inflammation. We have recently demonstrated that NGF positively regulates the transcriptional control regions in the rat TRPV1 gene. Based on additional data, we now propose to study a link between the Sp1- like family of transcription factors and NGF / inflammation mediated increases in TRPV1 dependent pain. 2) Another area of study is the regulation of TRPV1 expressed activity through its co-expression with other TRPV1 splice variants. Previously, we identified a TRPV1 splice variant (VR.5'sv) that when co-expressed, blocks TRPV1 activation to noxious stimuli in vitro. We now propose to study the physiologic consequence of VR.5'sv and other TRPV1 splice variants in individual sensory neurons. By studying the individual response properties of nociceptive neurons and matching these responses to a molecular signature of splice variant expression, we will determine the role of TRPV1 splice variants in the control of nociceptor activation and pain transduction.

Public Health Relevance

The basis for chronic pain arising from inflammatory conditions is poorly understood. The receptor that detects the burning sensation to pungent hot chili peppers is important for maintaining inflammatory pain in sensory nerves. We are studying a way to reduce or turn off the production of this receptor in sensory nerves as a way to control the pain from chronic peripheral inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038737-11
Application #
8312645
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Chen, Daofen
Project Start
1999-04-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$264,968
Indirect Cost
$93,468
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Chu, Catherine; Zavala, Kathryn; Fahimi, Atefeh et al. (2011) Transcription factors Sp1 and Sp4 regulate TRPV1 gene expression in rat sensory neurons. Mol Pain 7:44
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