Molecular analyses of primary afferent nociceptors have revealed remarkable heterogeneity. In addition to the traditional peptide and non-peptide classes of nociceptor, there is a complex array of thermal, mechanical and chemical transducers that define """"""""pain"""""""" fibers. Our laboratory research is focused on the nervous system mechanisms that underlie the development of persistent pain. Among the important questions are whether and the extent to which neurochemically-distinct nociceptor classes target different populations of spinal cord projection neurons, the extent to which different nociresponsive projection neurons engage different brain regions and the extent to which local (interneuronal) and descending circuits that influence one population of projection neuron are recapitulated for other spinal cord nociresponsive networks. Unfortunately, traditional neuroanatomical tract tracing methods cannot provide the answers to these questions. To overcome these limitations, we have developed powerful genetically-based transneuronal anterograde tracing methods to dissect the circuits engaged by distinct populations of nociceptor. The experiments outlined in Specific Aim 1 will continue these studies, focusing on the peptide, non- peptide and TRPV1 subsets of nociceptors. Using a very novel tracing method described in Specific Aim 2, we will also examine the circuits that influence the major populations of spinal cord projection neuron. We will use Cre-recombinase-dependent pseudorabies virus transneuronal retrograde tracing to study selectively the circuits that regulate different populations of spinal cord projection neuron. Finally, experiments in Specific Aim 3 will address the circuits that regulate the protein kinase C gamma subset of spinal cord interneurons, which we previously implicated in the generation of injury- induced persistent pain. Together our studies will not only provide information on the central nervous system circuits engaged by subsets of nociceptors, but will define important differences in the circuits that regulate what are clearly heterogeneous populations of nociresponsive spinal cord projection neurons. The information gained from these studies will contribute to the development of targeted pain therapies that are based on interrupting specific circuits that underlie particular pain conditions.

Public Health Relevance

Our laboratory has identified many of the molecular properties that underlie the incredible heterogeneity of the peripheral nerve fibers that respond to injury, which is the first step in the process through which tissue or nerve injury produces acute and, in pathological conditions, chronic pain. With a view to defining the neural circuits through which the information from the pain fibers is communicated to the spinal cord and brain, where the pain percept is eventually generated, we have developed powerful genetically-based neuroanatomical tracing methods that we will exploit in the proposed series of experiments. The information gained from these studies will contribute to the development of targeted pain therapies that are based on interrupting specific circuits that underlie particular pain conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS014627-36
Application #
8496132
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
1978-07-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
36
Fiscal Year
2013
Total Cost
$476,719
Indirect Cost
$163,093
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
Cevikbas, Ferda; Braz, Joao M; Wang, Xidao et al. (2017) Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis. J Allergy Clin Immunol 140:454-464.e2
Tran, May; Kuhn, Julia A; Bráz, João M et al. (2017) Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn. J Comp Neurol 525:3414-3428
Zhang, Chuchu; Medzihradszky, Katalin F; Sánchez, Elda E et al. (2017) Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release. Proc Natl Acad Sci U S A 114:E2524-E2532
Etlin, Alex; Bráz, Joao M; Kuhn, Julia A et al. (2016) Functional Synaptic Integration of Forebrain GABAergic Precursors into the Adult Spinal Cord. J Neurosci 36:11634-11645
Frezel, Noémie; Sohet, Fabien; Daneman, Richard et al. (2016) Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE. Exp Neurol 283:224-34
Basbaum, Allan I; Bráz, João M (2016) Cell transplants to treat the ""disease"" of neuropathic pain and itch. Pain 157 Suppl 1:S42-7
Guan, Zhonghui; Kuhn, Julia A; Wang, Xidao et al. (2016) Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 19:94-101
Osteen, Jeremiah D; Herzig, Volker; Gilchrist, John et al. (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534:494-9
Brown, Jacob D; Saeed, Maythem; Do, Loi et al. (2015) CT-guided injection of a TRPV1 agonist around dorsal root ganglia decreases pain transmission in swine. Sci Transl Med 7:305ra145
Petitjean, Hugues; Pawlowski, Sophie Anne; Fraine, Steven Li et al. (2015) Dorsal Horn Parvalbumin Neurons Are Gate-Keepers of Touch-Evoked Pain after Nerve Injury. Cell Rep 13:1246-1257

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