Molecular and Functional Changes of Dorsal Root Ganglion Neurons in a Rodent Model of Intervertebral Disc Degeneration

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2017

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Abstract

Low back pain affects up to 85% of the population in their lifetime and is strongly associated with degeneration of the intervertebral disc (IVD). Surgical lumbar disc puncture (LDP) in rodents is a widely used model of IVD degeneration due to the development of morphologic changes and evidence of altered pain-related functional measures. LDP models of IVD degeneration also show molecular changes in the dorsal root ganglia (DRGs) at less than 9 weeks post-injury, including alterations to markers of nerve growth factor (NGF)-dependent neurons. Lumbar disc puncture-induced inflammation can lead to local release of NGF, which acts on NGF receptors (TrkA, p75NTR) on the central terminals of DRG neurons innervating the IVD to play a role in pain development. TRPV1 function can be potentiated through NGF binding to these receptors, a mechanism often assessed in vitro via capsaicin challenge. The goal of this dissertation was to develop and characterize a surgical model of painful IVD degeneration in the rat, including a behavioral phenotype as well as NGF-related molecular and functional DRG neuron changes.

In the first part of this dissertation, the L5-L6 IVD in rats was surgically punctured and the behavioral phenotype was characterized until post-operative week 20 to assess development of discogenic pain. Secondly, capsaicin challenge experiments were performed in vitro to examine the functional implications of an NGF-related mechanism in discogenic pain. Finally, IVD degeneration was confirmed and immunostaining for NGF receptors was done to further investigate the involvement of NGF-related molecular mechanisms in painful IVD degeneration.

Findings revealed a timeline of pain-related behavioral changes, with evidence of LDP-related behavioral and gait changes at 16-18 weeks post-surgery. Additionally, this model produced a phenotype of clinically relevant, bilateral behavioral changes, including decreased overall activity as well as decreased hind limb stride frequency. Finally, DRG neurons showed NGF-related molecular and functional differences 20 weeks post-surgery. Ipsilateral DRG neurons showed impaired functionality of TRPV1 receptors and impaired TRPV1 receptor insertion into the cell membrane, as well as increased p75NTR expression. Contralateral neurons showed impaired TRPV1 functionality only. Bilateral DRGs showed increased transcriptional activity of both TRPV1-positive and TRPV1-negative neurons.

The studies in this dissertation support involvement of an NGF-related mechanism in painful IVD degeneration and establish the importance of utilizing a clinically relevant and longer-term model of IVD degeneration to investigate the specific mechanisms of pain generation.

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Leimer, Elizabeth Marie (2017). Molecular and Functional Changes of Dorsal Root Ganglion Neurons in a Rodent Model of Intervertebral Disc Degeneration. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/16366.

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