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 na?ve 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, GFR?, 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023725-26
Application #
8631183
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Jakeman, Lyn B
Project Start
1989-09-01
Project End
2018-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
26
Fiscal Year
2013
Total Cost
$427,275
Indirect Cost
$135,798
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jankowski, Michael P; Lawson, Jeffrey J; McIlwrath, Sabrina L et al. (2009) Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling. J Neurosci 29:1636-47
Jankowski, Michael P; McIlwrath, Sabrina L; Jing, Xiaotang et al. (2009) Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Res 1256:43-54
Rau, Kristofer K; McIlwrath, Sabrina L; Wang, Hong et al. (2009) Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J Neurosci 29:8612-9
Woodbury, C Jeffery; Kullmann, Florenta A; McIlwrath, Sabrina L et al. (2008) Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J Comp Neurol 508:500-9
Malin, Sacha A; Davis, Brian M; Koerber, H Richard et al. (2008) Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2. Pain 138:484-96
Elitt, Christopher M; Malin, Sacha A; Koerber, H Richard et al. (2008) Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil. Brain Res 1230:80-90
Lawson, Jeffrey J; McIlwrath, Sabrina L; Woodbury, C Jeffery et al. (2008) TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298-308
Woodbury, C Jeffery; Koerber, H Richard (2007) Central and peripheral anatomy of slowly adapting type I low-threshold mechanoreceptors innervating trunk skin of neonatal mice. J Comp Neurol 505:547-61
Koerber, H Richard; Mirnics, Karoly; Lawson, Jeffrey J (2006) Synaptic plasticity in the adult spinal dorsal horn: the appearance of new functional connections following peripheral nerve regeneration. Exp Neurol 200:468-79
Albers, Kathryn M; Woodbury, C Jeffrey; Ritter, Amy M et al. (2006) Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J Neurosci 26:2981-90

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