Pain resulting from inflammation of is one of the most common reasons people seek medical attention. Inflammatory pain is associated with the sensitization of primary afferent neurons innervating injured tissue; i.e., those arising from trigeminal ganglia (TG) or dorsal root ganglia (DRG). Pain arising from specific structures such as the colon or TMJ is often the most difficult pain to treat possibly reflecting the unique properties of these afferents and/or the unique structures these afferents innervate. Nevertheless, our present understanding of the neurobiology of sensory neurons and their response to injury is derived largely from studies on somatic afferents. ? ? In normal tissue, voltage- and Ca2+-activatedchannels present in the plasma membrane of the afferent terminal control afferent excitability. Primary afferent neurons are hyper-excitable in the presence of persistent inflammation. However little is known about the mechanisms underlying this increase in excitability? This is particularly true for visceral and joint afferents given the dearth of data on the basic membrane properties of these afferents innervating normal tissue. One class of ion channels that may be particularly important for the expression of inflammation-induced hyperexcitability is Ca2+activated K+(CaK) channels. Inhibition of CaK channels appears to underlie sensitization of vagal afferents following airway inflammation and our preliminary data suggest that these channels are likely to contribute to inflammation-induced changes in the excitability DRG and TG neurons innervating several structures. Importantly, there have been only two studies on the function of CaK channels in sensory neurons from naive animals and none on the function of CaK channels in sensory neurons from inflamed animals. Therefore, we propose to test the following hypotheses: 1) that the distribution and functional role of CaK channels varies with respect to target of innervation (i.e., colon, TMJ, muscle and skin); and 2) that inflammation results in changes in the pattern of expression of CaK channels, which underlies changes in excitability that are unique to specific targets of innervation. We will test these hypotheses in experiments described under 2 Specific Aims employing a combination of retrograde tracing, in vitro patch-clamp electrophysiology, Ca2+imaging and RT-PCR analysis on adult rats either in the presence of absence of inflammation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS044992-05
Application #
7342698
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Porter, Linda L
Project Start
2003-06-01
Project End
2009-05-31
Budget Start
2006-10-01
Budget End
2009-05-31
Support Year
5
Fiscal Year
2006
Total Cost
$344,019
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Scheff, Nicole N; Lu, Shao-Gang; Gold, Michael S (2013) Contribution of endoplasmic reticulum Ca2+ regulatory mechanisms to the inflammation-induced increase in the evoked Ca2+ transient in rat cutaneous dorsal root ganglion neurons. Cell Calcium 54:46-56
Zhang, Xiu-Lin; Mok, Lee-Peng; Lee, Kwan Yeop et al. (2012) Inflammation-induced changes in BK(Ca) currents in cutaneous dorsal root ganglion neurons from the adult rat. Mol Pain 8:37
Lu, Shao-Gang; Zhang, Xiu-Lin; Luo, Z David et al. (2010) Persistent inflammation alters the density and distribution of voltage-activated calcium channels in subpopulations of rat cutaneous DRG neurons. Pain 151:633-43
Zhang, Xiu-Lin; Mok, Lee-Peng; Katz, Elizabeth J et al. (2010) BKCa currents are enriched in a subpopulation of adult rat cutaneous nociceptive dorsal root ganglion neurons. Eur J Neurosci 31:450-62
Price, Theodore J; Cervero, Fernando; Gold, Michael S et al. (2009) Chloride regulation in the pain pathway. Brain Res Rev 60:149-70
Goss, J R; Gold, M S; Glorioso, J C (2009) HSV vector-mediated modification of primary nociceptor afferents: an approach to inhibit chronic pain. Gene Ther 16:493-501
Zhang, X-L; Gold, M S (2009) Dihydropyridine block of voltage-dependent K+ currents in rat dorsal root ganglion neurons. Neuroscience 161:184-94
Gupta, Gopal N; Lu, Shao-Gang; Gold, Michael S et al. (2009) Bladder urothelial cells from patients with interstitial cystitis have an increased sensitivity to carbachol. Neurourol Urodyn 28:1022-7
Anseloni, Vanessa C Z; Gold, Michael S (2008) Inflammation-induced shift in the valence of spinal GABA-A receptor-mediated modulation of nociception in the adult rat. J Pain 9:732-8
Gold, Michael S (2008) Na(+) channel blockers for the treatment of pain: context is everything, almost. Exp Neurol 210:1-6

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