MOLECULAR MECHANISMS OF AGING IN THE PERIPHERAL NOCICEPTIVE SYSTEM Shuying Wang MD, PhD University of Pittsburgh, 2006 Decreased pain sensitivity during aging is common in humans and animals and is largely due to changes in anatomical, functional and cellular properties of the peripheral nervous system (PNS). To understand the molecular mechanisms of aging in the PNS, a detailed comparative study was made of 6~8week-, 16month- and 2year-old Blk6 male mice obtained from the NIA mouse colony. Behavioral assays showed aged mice had decreased sensitivity to noxious heat and impaired inflammation-induced thermal hyperalgesia compared to young animals. To understand the basis for this change we examined expression of the growth factor artemin, its receptor GFRα3 and TRPV1, an ion channel expressed by 95~99% of GFRα3-positive sensory neurons. TRPV1 is of significance since it is required for transmission of thermal hyperalgesia following tissue inflammation. Assays showed a reduction in TRPV1 mRNA and protein in the PNS of aged mice that correlated with a decrease in expression of the artemin receptor GFRα3, CFA-induced inflammation also increased artemin expression in the skin but decreased expression of GFRα3 in the dorsal root ganglia (DRG) of both young and old mice. The decrease in GFRα3 was greater in aged mice, suggesting GFRα3 signaling following CFA is reduced in sensory ganglia of old mice and that the response properties of GFRα3-positive sensory neurons that express TRPV1 are diminished. Calcium imaging of isolated primary neurons grown with NGF was used to test the in vitro effects of artemin on TRPV1 expression and activation in young and old neurons. Artemin potentiated TRPV1 activation by capsaicin in both young and old neurons, but the amplitude of capsaicin responses in young neurons was decreased with long-term exposure to artemin. Microarray and RT-PCR studies revealed that inflammation-associated genes such as interleukin 6 (IL-6) were elevated in sensory ganglia of aged mice. This ongoing inflammatory state may increase the inflammatory tone of the system and thereby contribute to changes in response properties and sensitivity of sensory neurons in the aging PNS. Thus, the reduced sensitivity to inflammatory pain in aged animals likely reflects a combination of changes in anatomical, physiologic and immune response properties.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11272006-155805 |
| Date | 20 March 2007 |
| Creators | Wang, Shuying |
| Contributors | Kathryn M. Albers, Ph.D., Stephen W. Scheff, Ph.D., Carl F. Lagenaur, Ph.D, H. Richard Koerber, Ph.D., Brian M. Davis, Ph.D., J. Patrick Card, Ph.D |
| 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-11272006-155805/ |
| 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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