Behavioral Compensations and Neuronal Remodeling in a Rodent Model of Chronic Intervertebral Disc Degeneration

Elizabeth M Leimer,Matthew G Gayoso,Liufang Jing,Simon Y Tang,Munish C Gupta,Lori A Setton

doi:10.1038/s41598-019-39657-6

Abstract

Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.

Highlights

43 New Scotland Ave, Albany, NY, 12208, USA
NGF binding to tyrosine kinase A (TrkA) regulates collateral sprouting of sympathetic fibers to dorsal root ganglion (DRG) neurons that may relate to maintenance of chronic pain[22] and can acutely sensitize sensory neurons to capsaicin[19]
Different changes in unilateral parameters began at post-operative weeks 16 (Supplementary Fig. S2c,d) and 18 (Supplementary Fig. S2a), as well as bilateral changes at post-operative week 18 (Supplementary Fig. S2e). These results revealed a distinct timeline of behavioral changes after Lumbar disc puncture (LDP) injury: acute changes induced by surgical trauma resolved at 4–6 weeks post-surgery, a period resembling pre-surgical values was sustained from 6–16 weeks post-surgery, and changes were again observed at 16–20 weeks post-surgery

Summary

Introduction

43 New Scotland Ave, Albany, NY, 12208, USA. Correspondence and requests for materials should be addressed to www.nature.com/scientificreports/. LDP in animal models induces transient upregulation of pro-inflammatory cytokines in the IVD, including TNF-α and IL-1β, compared to more persistent upregulation which has been widely observed in human pathological samples[11,14] These pro-inflammatory cytokines are known to induce regulators of pain, including NGF and substance P mRNA expression and protein secretion[15,16]. NGF binding to TrkA regulates collateral sprouting of sympathetic fibers to DRG neurons that may relate to maintenance of chronic pain[22] and can acutely sensitize sensory neurons to capsaicin[19] In this context, we hypothesized that molecular changes in the degenerated IVD following lumbar disc puncture could contribute to an adaptive sensory neuron response that may be active in chronic IVD degeneration and play a role in discogenic pain

Methods

Results

Conclusion