The goal of the proposed studies is to examine the time course of changes in identified cutaneous sensory neurons and spinal cord neurons responsible for the development and maintenance of inflammatory and neuropathic pain states. These neurons play critical roles in processing of pain information. These studies will address three specific aims. In the first aim we will employ combined physiological and anatomical techniques to determine the properties of primary afferents and superficial dorsal horn cells in normal mice. In the second aim we will determine the properties of the same cells after inflammatory and neuropathic injury. Behavioral tests of mechanical and heat sensitivity will be compared with any changes seen in the identified neurons. In the third aim, we will use two trangenic mouse lines (one that has the capsaicin/heat channel TRPV1 knocked out, one that has the Mas-gene related G-protein coupled receptor D (Mrgdprd) knocked out and green fluorescent protein knocked in). TRPV1 has been shown to mediate some aspects of heat sensitivity, and Mrgprd is found exclusively in a population of cutaneous sensory nociceptors. We have recently found that these cutaneous nociceptors in Mrgprd-knock-out mice, have attenuated heat responses. We will determine the properties of primary afferent and secondary nociceptors in these two mouse lines following inflammatory and neuropathic injury. By comparing behavioral and neural data, we will be able to assess the effect of these genetic manipulations on the induction and maintenance of pain states following two types of injury. The data gathered in all three specific aims will be used to develop a model of neural circuits that are essential during these pain states. By comparing the three groups, we hope to elucidate the specific populations of primary afferent and secondary nociceptive neurons crucial to this process.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-K (02))
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Porter, Linda L
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University of Pittsburgh
Schools of Medicine
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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
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
Jankowski, Michael P; Rau, Kristofer K; Soneji, Deepak J et al. (2012) Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation. Pain 153:410-9
Molliver, Derek C; Rau, Kristofer K; McIlwrath, Sabrina L et al. (2011) The ADP receptor P2Y1 is necessary for normal thermal sensitivity in cutaneous polymodal nociceptors. Mol Pain 7:13
Li, Lishi; Rutlin, Michael; Abraira, Victoria E et al. (2011) The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147:1615-27
Koerber, H Richard; McIlwrath, Sabrina L; Lawson, Jeffrey J et al. (2010) Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers. Mol Pain 6:58
Jankowski, Michael P; Rau, Kristofer K; Soneji, Deepak J et al. (2010) Enhanced artemin/GFR?3 levels regulate mechanically insensitive, heat-sensitive C-fiber recruitment after axotomy and regeneration. J Neurosci 30:16272-83
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

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