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Dissertation
Modulation of TRPV1, nociceptor sensitization , and induction of thermal hyperalgesia by C-type natriuretic peptide
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2013
DOI: 10.17077/etd.eeifhk77
Abstract
<p>Rheumatoid arthritis (RA) is caused by aberrant attack of the joints by native inflammatory system. This can lead to joint destruction and pain that can be debilitating. Increased angiogenesis and innervation by nociceptive afferent fibers are characteristic features of RA joints, which in addition to the elevated levels of a wide variety of inflammatory mediators, are thought to play an important role in the pathogenesis of chronic inflammatory pain associated with RA. Interestingly, a recent report indicates that C–type natriuretic peptide (CNP) is increased in the blood serum of RA patients. Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Many biological effects of NPs are mediated by guanylate cyclase (GC)–coupled NP receptors, NPR–A and NPR–B, whereas the third NP receptor, NPR–C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR–C can couple to specific G<sub>ái<sub>–βã–mediated intracellular signaling cascades in numerous cell types. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain largely unknown.</p>
<p>In Aim 1, I show that CNP acutely sensitized the excitation of mouse dorsal root ganglia (DRG) sensory neurons that is dependent on the transient receptor potential vanilloid–1 (TRPV1). CNP potentiated capsaicin– and proton–activated TRPV1 currents in cultured mouse DRG neurons and increased neuronal firing frequency, an effect that was absent in DRG neurons from <em>TRPV1<em><sup>−/−<sup>mice. Further, CNP injection into mouse hind paw led to the development of thermal hyperalgesia, which was absent in <em>TRPV1<em><sup>−/−<sup>mice.</p>
<p>In Aim 2, I dissected the signaling mechanism underlying TRPV1 sensitization by CNP. My results show that all 3 functional NPRs are expressed in mouse DRG neurons; however NPR–A/B–cGMP signaling is not involved in CNP–mediated sensitization of TRPV1. Interestingly, I observed that sensitization of TRPV1 by CNP is dependent on protein kinase C (PKC) activity. Furthermore, I found that NPR–C is co–expressed in TRPV1–expressing mouse DRG neurons and can be co–immunoprecipitated with G<sub>αi<sub>, but not with G<sub>αq/11<sub> or G<sub>αs<sub> subunits. CNP treatment induced translocation of PKCå to the plasma membrane of these neurons, which was attenuated by pertussis toxin pre–treatment. Accordingly, CNP–induced sensitization of TRPV1 was attenuated by pre–treatment of DRG neurons with the specific inhibitors of G<sub>βã<sub>, phospholipase–Cβ (PLCβ) or PKC, but not of protein kinase A (PKA), and by mutations at two PKC phosphorylation sites, S502 and S800, in the TRPV1 protein. Furthermore, the development of thermal hyperalgesia in CNP–injected hindpaw was attenuated by administration of specific inhibitors of G<sub>βã<sub> or PKC. Thus, my work identifies the G<sub>βã<sub>–PLCâ–PKC–dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity. Such signaling cascade could presumably constitute one of the mechanisms underlying chronic inflammatory joint pain associated with RA.</p>
Details
- Title: Subtitle
- Modulation of TRPV1, nociceptor sensitization , and induction of thermal hyperalgesia by C-type natriuretic peptide
- Creators
- Lipin Loo - University of Iowa
- Contributors
- D. P. Mohapatra (Advisor)Christopher J. Benson (Committee Member)Timothy J Brennan (Committee Member)Donna L. Hammond (Committee Member)Yuriy M. Usachev (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Spring 2013
- Publisher
- University of Iowa
- DOI
- 10.17077/etd.eeifhk77
- Number of pages
- xviii, 91 pages
- Copyright
- Copyright 2013 Lipin Loo
- Language
- English
- Description illustrations
- illustrations (some col.)
- Description bibliographic
- Includes bibliographical references (pages 80-91).
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9983777075802771
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