| Type of Document |
Dissertation |
| Author |
Wang, Shuying
|
| URN |
etd-11272006-155805 |
| Title |
MOLECULAR MECHANISMS OF AGING IN THE PERIPHERAL NOCICEPTIVE SYSTEM |
| Degree |
Doctor of Philosophy |
| Program |
Neurobiology |
| School |
School of Medicine |
| Advisory Committee |
| Advisor Name |
Title |
| Kathryn M. Albers, Ph.D. |
Committee Chair |
| H. Richard Koerber, Ph.D. |
Committee Co-Chair |
| Brian M. Davis, Ph.D. |
Committee Member |
| Carl F. Lagenaur, Ph.D |
Committee Member |
| J. Patrick Card, Ph.D |
Committee Member |
| Stephen W. Scheff, Ph.D. |
Committee Member |
|
| Keywords |
- Calcium imaging
- Inflammation
- Aging
- Pain
- TRPV1
- DRG
- Artemin
|
| Date of Defense |
2006-12-14 |
| Availability |
unrestricted |
Abstract
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.
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