Sensory neurons responsive to painful stimuli, called nociceptors, are crucial for the health of an organism as they are responsible for initiating behavioral responses that prevent or limit tissue damage. Under normal circumstances pain is an important sensation. However, following injury or disease, pain can become persistent, seriously disrupting the lives of those affected. Development and maintenance of nociceptors is known to be dependent on two growth factors, nerve growth factor (NGF) and glial-line derived neurotrophic factor (GDNF). Furthermore, it has been proposed that NGF and GDNF support two different populations of nociceptors and that these two populations are responsible for different types of persistent pain. In addition, changes in nociceptor function induced by NGF and GDNF also modulate nociceptive processing in the adult spinal cord, suggesting a multi-level, growth factor-driven plasticity in the somatosensory system. In our previous studies we determined that NGF plays a dramatic role in determining the """"""""comprehensive phenotype"""""""" of nociceptors, influencing physiological, anatomical and functional properties of NGF-dependent nociceptors. The next step is to determine how GDNF affects nociceptors, how changes in NGF and GDNF affect spinal cord neurons receiving nociceptive input, and what affects these changes have on persistent pain. This proposal consists of three Specific Aims employing a """"""""genes to behavior"""""""" approach.
Specific Aim 1 examines how increases in the level of GDNF affects the comprehensive phenotype of nociceptors. This data will be compared with the results from the NGF studies to provide a complete analysis of the role of growth factors in nociceptor development.
Specific Aim 2 examines how NGF- and GDNF- induced changes in nociceptors affects dorsal horn anatomy and neurochemistry. Analysis of spinal cord is crucial because alteration in spinal cord homeostasis can exacerbate or compensate for persistent pain.
Specific Aim 3 examines how mice with hypertrophied NGF and GDNF phenotypes respond in two models of persistent pain. Whole animal behavior, nociceptor physiology and changes in dorsal horn neurochemistry will be examined. Upon completion of these specific aims, we anticipate that the differences between NGF- dependent and GDNF-dependent nociceptors will be understood with respect to their anatomical, physiological and neurochemical traits. In addition, it should be possible to identify how these two classes of nociceptors affect dorsal horn development and function. Finally, we will gain insight into how these two classes of nociceptors and their spinal cord targets, respond to induction of persistent pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031826-11
Application #
6529461
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Mamounas, Laura
Project Start
1993-05-01
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
11
Fiscal Year
2002
Total Cost
$481,145
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Smith-Edwards, Kristen M; DeBerry, Jennifer J; Saloman, Jami L et al. (2016) Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators. Elife 5:
DeBerry, Jennifer J; Schwartz, Erica S; Davis, Brian M (2014) TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis. Pain 155:1280-7
Wang, Ting; Jing, Xiaotang; DeBerry, Jennifer J et al. (2013) Neurturin overexpression in skin enhances expression of TRPM8 in cutaneous sensory neurons and leads to behavioral sensitivity to cool and menthol. J Neurosci 33:2060-70
Wang, Ting; Molliver, Derek C; Jing, Xiaotang et al. (2011) Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury. PLoS One 6:e28908
Malin, Sacha; Molliver, Derek; Christianson, Julie A et al. (2011) TRPV1 and TRPA1 function and modulation are target tissue dependent. J Neurosci 31:10516-28
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
Malin, Sacha A; Christianson, Julie A; Bielefeldt, Klaus et al. (2009) TPRV1 expression defines functionally distinct pelvic colon afferents. J Neurosci 29:743-52
Stucky, Cheryl L; Dubin, Adrienne E; Jeske, Nathaniel A et al. (2009) Roles of transient receptor potential channels in pain. Brain Res Rev 60:2-23
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

Showing the most recent 10 out of 41 publications