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.
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.
|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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