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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (51))
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Kusiak, John W
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Johns Hopkins University
Schools of Medicine
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Orefice, Lauren L; Zimmerman, Amanda L; Chirila, Anda M et al. (2016) Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs. Cell 166:299-313
Emery, Edward C; Luiz, Ana P; Sikandar, Shafaq et al. (2016) In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP. Sci Adv 2:e1600990
Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook et al. (2016) Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain. Neuron 91:1085-96
Bai, Ling; Lehnert, Brendan P; Liu, Junwei et al. (2015) Genetic Identification of an Expansive Mechanoreceptor Sensitive to Skin Stroking. Cell 163:1783-95
Weng, Hao-Jui; Patel, Kush N; Jeske, Nathaniel A et al. (2015) Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain. Neuron 85:833-46
Han, Liang; Dong, Xinzhong (2014) Itch mechanisms and circuits. Annu Rev Biophys 43:331-55
Wooten, Matthew; Weng, Hao-Jui; Hartke, Timothy V et al. (2014) Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun 5:4122
Hua, Zhong L; Jeon, Sangmin; Caterina, Michael J et al. (2014) Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system. Proc Natl Acad Sci U S A 111:E3005-14
Zimmerman, Amanda; Bai, Ling; Ginty, David D (2014) The gentle touch receptors of mammalian skin. Science 346:950-4
Caterina, Michael J (2014) TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci 5:1107-16

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