Chronic pain following acute peripheral nerve injury is a major public health issue. Our primary goal in this proposal is to understand the cellular processes that underlie plasticity in cutaneous and muscle sensory neurons following injury and regeneration. Specifically, we will look at injury-induced plasticity of primary sensory neurons reinnervating either skin or striated muscle. In the first aim, we use ex vivo skin or muscle/nerve/DRG/spinal cord preparations and our novel method for recovering individual functionally characterized sensory neurons to determine the comprehensive phenotypes of cutaneous C-fibers and Group IV muscle afferents in naive mice. This includes characterization of the gene expression profiles of the individual functionally characterized fibers. In our preliminary studies we have indentified several unique functional classes of these fibers. In the second aim, we will first examine the effects of nerve injury on the functional properties and correlated changes in gene expression in individual characterized fibers reinnervating skin or muscle. In our preliminary studies we have confirmed and expanded upon earlier studies showing that these fibers are sensitized following regeneration. In addition, our results suggest that some fibers are changing phenotype. Next we will examine changes in DRG expression of specific trk, GFRalpha, ASIC, TRP and purinergic receptors/channels contained in these fibers to indentify possible molecular mechanisms responsible for the changes in function observed following nerve injury and regeneration. In the third aim, we will use our novel in vivo siRNA knockdown technique to test the hypothesis that the injury-induced increase in the expression of particular receptors/channels (e.g. ASIC, TRP and purinergic) mediates the observed functional plasticity in specific populations of cutaneous and muscle afferents. For example, we expect to find that knockdown of the increase in TRPM3 expression levels following cutaneous nerve injury and regeneration will block the observed sensitization of cutaneous C-polymodal fibers to heat. Similarly we expect that knockdown in ASIC3 expression following muscle nerve injury and regeneration will block the sensitization of muscle afferents to mechanical stimulation. The determination of the specific receptors/channels responsible for sensitization of these fibers will provide new insights to these processes and more importantly could provide potential targets for the development of pharmaceutical therapies. These new therapies could provide for improved treatments for the alleviation of the adverse symptoms of chronic neuropathic pain.

Public Health Relevance

Injury to peripheral nerves often leads to a variety of clinical disorders including chronic pain syndromes. In this application we are proposing to determine specific nerve injury-induced cellular and molecular changes in cutaneous and muscle sensory neurons that could lead to these clinical disorders. Determination of these mechanisms could provide targets for new pharmaceutical therapies that could provide for improved functional recovery following nerve regeneration, as well as, alleviation of the adverse syndromes of neuropathic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Jakeman, Lyn B
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University of Pittsburgh
Schools of Medicine
United States
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Jankowski, Michael P; Rau, Kristofer K; Koerber, H Richard (2017) Cutaneous TRPM8-expressing sensory afferents are a small population of neurons with unique firing properties. Physiol Rep 5:
Jankowski, Michael P; Baumbauer, Kyle M; Wang, Ting et al. (2017) Cutaneous neurturin overexpression alters mechanical, thermal, and cold responsiveness in physiologically identified primary afferents. J Neurophysiol 117:1258-1265
Hachisuka, Junichi; Baumbauer, Kyle M; Omori, Yu et al. (2016) Semi-intact ex vivo approach to investigate spinal somatosensory circuits. Elife 5:
Reed-Geaghan, Erin G; Wright, Margaret C; See, Lauren A et al. (2016) Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes. J Neurosci 36:4362-76
Molliver, Derek C; Rau, Kristofer K; Jankowski, Michael P et al. (2016) Deletion of the murine ATP/UTP receptor P2Y2 alters mechanical and thermal response properties in polymodal cutaneous afferents. Neuroscience 332:223-30
Baumbauer, Kyle M; DeBerry, Jennifer J; Adelman, Peter C et al. (2015) Keratinocytes can modulate and directly initiate nociceptive responses. Elife 4:
Kardon, Adam P; Polgár, Erika; Hachisuka, Junichi et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573-86
Vrontou, Sophia; Wong, Allan M; Rau, Kristofer K et al. (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493:669-73
Jankowski, Michael P; Rau, Kristofer K; Ekmann, Katrina M et al. (2013) Comprehensive phenotyping of group III and IV muscle afferents in mouse. J Neurophysiol 109:2374-81
Jankowski, Michael P; Soneji, Deepak J; Ekmann, Katrina M et al. (2012) Dynamic changes in heat transducing channel TRPV1 expression regulate mechanically insensitive, heat sensitive C-fiber recruitment after axotomy and regeneration. J Neurosci 32:17869-73

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