Looking beyond the intervertebral disc: the need for behavioral assays in models of discogenic pain

Abstract

Orthopedic research into chronic discogenic back pain has commonly focused on aging- and degeneration-related changes in intervertebral disc structure, biomechanics, and biology. However, the primary spine-related reason for physician office visits is pain. The ambiguous nature of the human condition of discogenic low back pain motivates the use of animal models to better understand the pathophysiology. Discogenic back pain models must consider both emergent behavioral changes following pain induction and changes in the nervous system that mediate such behavior. Looking beyond the intervertebral disc, we describe the different ways to classify pain in human patients and animal models. We describe several behavioral assays that can be used in rodent models to augment disc degeneration measurements and characterize different types of pain. We review rodent models of discogenic pain that employed behavioral pain assays and highlight a need to better integrate neuroscience and orthopedic science methods to extend current understanding of the complex and multifactorial pathophysiology of discogenic back pain.

Keywords: behavior; discogenic pain; intervertebral disc; nervous system; rodent model.

Figure 1

Pain types and how they are measured in rodent models.

Figure 2

IVD degeneration–related pain has greater variance than IVD degeneration. IVD degeneration and pain do not have a linear relationship, as demonstrated by two animals with similarly degenerated IVDs having vastly different mechanical paw-withdrawal thresholds. Both animals exhibited reduced mechanical paw withdrawal thresholds during the acute postoperative period, but animal A recovered to a greater extent than Animal B. (A and B) Mid-sagittal sections of rat lumbar IVDs stained with safranin-O/light green exhibited equal degeneration grades as determined by a semiquantitative histological grading scale of a total grade (0–10, least to most degenerated) of AF integrity, AF/NP border definition, NP cellularity, NP matrix condensation, and CEP regularity made by two graders at two time points. (C) Mechanical paw-withdrawal thresholds of corresponding rats normalized to presurgery values exhibited variability. Pain behavior evaluated using the von Frey assay. Scale bars = 250 μm.

Figure 3

Pain pathway from the intervertebral disc to the brain. Following IVD degeneration, pain may be evoked by a variety of possible mechanisms, such as nerve root irritation, neurovascular ingrowth, sensitized peripheral nerves, and/or abnormal concentrated stresses. Peripheral Aδ and C fibers transmit pain signals from the IVD and adjacent structures to the central nervous system. The cell bodies of these afferent peripheral nerves form the dorsal root ganglia. Within the spinal cord, Aδ and C fibers synapse with ascending neurons in the dorsal horn, which carry the pain signal to the brain. Thus, modulation of the pain pathway can occur at multiple hubs in the pain pathway: at the site of injury, in the dorsal root ganglion, in the dorsal horn of the spinal cord, or within the brain.