Inadequate treatment of pain imposes an enormous burden on society, and is due, in part, to a limited understanding of biological events that underlie the transition from acute to chronic pain. Barriers to a better understanding of this transition have included an inability to selectively and efficiently visualize or manipulate specifc sensory neuron populations and the very low throughput of available methods to monitor nociceptor function at the cellular level. In this collaborative proposal, we have teamed together a developmental neurobiologist and several pain biologists to synergistically overcome both of these barriers. Using newly- developed molecular-genetic strategies, we will selectively label each of the four major subpopulations of low- threshold mechanoreceptive (LTMR) neurons, as well as peptidergic and MrgprD-expressing nonpeptidergic nociceptors, in mice. This technology will be combined with selective expression of the genetically encoded calcium indicator, GCAMP3, in mouse peripheral sensory neurons to permit direct visualization of neuronal activity in the skin and DRG. In our first two aims, these tools will allow us to efficiently and with high spatiotemporal resolution monitor changes in the anatomy and function of unambiguously defined nociceptor and LTMR populations during the development of neuropathic pain. These changes will be correlated with corresponding behavioral changes, monitored using classical and newly developed assays of thermal and mechanical sensitivity.
In Aim 3, we will selectively ablate two LTMR populations that are candidate participants in pain and define their respective contributions to the establishment, maintenance, and manifestation of neuropathic mechanical hypersensitivity. Together, these studies will provide us with an unprecedented view of the dynamic processes associated with the transition to chronic pain and define cellular targets for the development of improved analgesic therapies.

Public Health Relevance

Chronic pain affects millions of people and is often difficult to treat. This is due, in part, to our poor understanding of why some people, but not others, transition to a state of chronic pain after nerve injury. In this proposal, we will take advantage f new technology to directly visualize specific classes of nerves in the skin to understand how changes in their structure and function after nerve injury enhances the perception of pain. This will allow the rational development of improved therapies to treat chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022750-02
Application #
8518294
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (51))
Program Officer
Kusiak, John W
Project Start
2012-07-30
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$603,023
Indirect Cost
$230,787
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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