Chronic pain is a major clinical problem. Target-derived growth factors have been implicated in the initiation and maintenance of persistent pain states. Artemin, a member of the glial cell line-derived neurotrophic factor (GDNF) family, binds to its GPI-anchored receptor, GFRá3, and initates intracellular signaling via the tyrosine kinase, Ret. Expression of the GFRá3 receptor is largely restricted to the peripheral nervous system and is found in a subpopulation of nociceptive sensory neurons of the dorsal root and trigeminal ganglia (DRG & TG) that coexpress the Ret and TrkA receptor tyrosine kinases and the thermosensitive channel TRPV1. To investigate the role of artemin in regulating nociceptor properties and function, we isolated transgenic mice that overexpress artemin in keratinized tissues (ART-OE). Expression of artemin increased DRG neuron number, confirming the survival promoting effects of artemin. In addition, ART-OE mice had increased mRNA encoding GFRá3, TrkA, TRPV1 and the putative noxious cold and mustard oil detecting channel, TRPA1. Immunolabeling showed that nearly all GFRá3-positive neurons expressed TRPV1 and most of these neurons were also TRPA1-positive. Somas of GFRá3/TRPV1-positive neurons in the ART-OE mice were hypertrophied and there was increased staining for these proteins in the periphery. Interestingly, increases in TRPV1 and TRPA1 mRNA were more robust in TG than DRG. Because of these differential effects, lingual afferents innervating the heavily keratinized tongue were also examined. Retrogradely-labeled lingual afferents from ART-OE tongues showed an increased percentage of GFRá3- and TRPV1-positive neurons. Behavior analysis showed that these anatomical changes were correlated with increased sensitivity to noxious heat, noxious cold, capsaicin and mustard oil applied to the hindpaw, as well as oral sensitivity to capsaicin and mustard oil placed in the drinking water of these mice. Functional analysis of dissociated sensory neurons using calcium imaging showed hypersensitivity to capsaicin and mustard oil in trigeminal neurons isolated from ART-OE mice, and even greater sensitivity in the lingual subpopulation. Taken together, these results indicate that artemin promotes the survival and modulates functional properties of a select population of TRPV1- and TRPA1-positive nociceptors critical for the detection of noxious thermal and chemical stimuli in both cutaneous and lingual systems.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09262006-195831 |
| Date | 27 September 2006 |
| Creators | Elitt, Christopher Michael |
| Contributors | J. Patrick Card, PhD, Carl F. Lagenaur, PhD, Kathryn M. Albers, PhD, H. Richard Koerber, PhD, Brian M. Davis, PhD, Douglas E. Wright, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09262006-195831/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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