Discopathy and degenerative disc disease
Pain beyond anatomopathological determinism
Short review
Pathos 2026; 33.3. Online 2026, Sep 24
___________________________________________________________________________________
Claudio Santoro,1-2 Michela D’Oro,1 Compierchio Angelo,3
1Istituto di Abilitazione Neuromotoria, OsteoMedica, Benevento, Italia
2 European Institute of Technology, Rep. San Marino
3 Luleå University of Technology, Luleå, Sweden
_____________________________________________________________________________________
Summary
The aim of this review is to analyse the data available in the literature concerning the dynamics associated with pain perception in cases of discopathy and intervertebral disc degeneration. Determined by multifactorial factors, within the optimisation of the assessment processes typical of evidence-based medicine (EBM), discopathy – that is, intervertebral disc degeneration – and pain in the lumbar or cervical regions represent different stages of the same degenerative process, clearly linked to dysfunctional mechanical conditions. The complexity of the diagnostic procedure stems from the difficulty of distinguishing clinical findings from imaging findings, or rather, of interpreting the latter in the light of a pain physiology that has been largely overlooked, which encompasses aspects of histology, neurophysiology and neuropathology.
Riassunto
L'obiettivo di questa review è analizzare i dati disponibili in letteratura riguardanti le dinamiche associate alla percezione del dolore in presenza di discopatia e degenerazione del disco intervertebrale. Determinati da fattori multifattoriali, nell'ottimizzazione dei processi valutativi tipici della medicina basata sulle evidenze (EBM), la discopatia, ovvero la degenerazione del disco intervertebrale, e il dolore in area lombare o cervicale, risultano fasi diverse di uno stesso processo degenerativo, evidentemente legato a condizioni meccaniche disfunzionali. La complessità della procedura diagnostica è attribuibile alla difficoltà di separare la clinica dalla diagnostica per immagini, ovvero di valutare quest'ultima alla luce di una fisiologia del dolore poco considerata, che include gli aspetti dell'istologia, della neurofisiologia e della neuropatologia.
Parole chiave
Dolore nocicettivo, degenerazione, disco intervertebrale, lombalgia, dolore neuropatico
Key words
Nociceptive pain, degeneration, intervertebral disc, lumbosacral pain, neuropathic pain
Introduction
In cases of prolonged or disabling suffering in the cervical or lumbar areas, discs and nerve roots are the first structural elements to be taken into consideration, especially if the pain extends to the limbs.
The term 'discopathy' generally refers to weakening or damage to the intervertebral disc, such as protrusions, herniations or extrusions. Discopathy is classified as degenerative when there is a loss of proteoglycans, resulting in degeneration of the outer disc structure and dehydration of the nucleus pulposus. In the most advanced stages, these conditions lead to a significant reduction in the infrasomatic space, thereby diminishing the disc's resistance to functional loads.
Symptoms are commonly classified according to their cause, intensity and duration. In the case of the lumbar region, they are defined as 'pain and discomfort below the costal margin and above the lower gluteal folds, with or without referred pain to the leg.1
The consistently observed state of suffering tends to exhibit the characteristics of nociceptive pain. Receptor activation can be triggered by various stimuli that exceed a specific intensity threshold and are capable of causing actual or perceived mechanical, thermal or chemical damage to muscles, nerves, blood vessels within tissues or bone, the periosteal sheath and associated synovial capsular tissues. That said, it is frequently observed that:
- herniations are present even in asymptomatic individuals 2
- the same pain can manifest in the absence of herniation or disc degeneration.
- symptoms subside following conservative treatment;
- adopting pain-relieving postures can allow symptoms to resolve spontaneously.
While highlighting the significant discrepancy between scientific evidence and common clinical practice, pain syndromes affecting the lumbar, lumbocrural or lumbosciatic regions (as well as the cervical or cervicobrachial regions) are usually directly associated with discopathy, whether degenerative or otherwise. However, as in approximately 90–95% of cases the pain presents non-specific characteristics, it would be inappropriate to attribute it to a single factor, such as a herniated disc or disc degeneration.3
Disc degeneration
The gradual alteration of postural alignment, evidently resulting from repeated mechanical stresses or a progressive inability to withstand axial compression adequately, creates the ideal conditions for disc degeneration.
Historical research and literature attribute the occlusive capacities of the foramen (compression and inflammation of the nerve roots) to the nucleus pulposus escaping the annulus. In fact, it is stated that, assimilated to a foreign body, the hernia would trigger an immune system reaction aimed at releasing mast cells, histamine, IgG antibodies, neuropeptides and cytokines (interleukins 1β and 6), which are capable of increasing excitatory synaptic transmission in the dorsal horn of the spinal cord and have an allodynic-hyperalgesic effect, thereby developing an inflammatory reaction and exciting local nociceptors. Nevertheless, international literature suggests that between 25 and 50 percent of the healthy population experience asymptomatic disc herniation 2 (with higher rates among the elderly). This is attributed to the immune response that occurs in three stages when the nucleus pulposus extrudes from the disc.
This is due to the immune response, which occurs in three stages when the nucleus pulposus protrudes from the disc.
- M1-type macrophages (pro-inflammatory) intervene by producing cytokines such as TNF-α and IL-1β. This is the acute phase, during which nociceptive activation leading to the onset of pain may occur.
- The extruded nucleus pulposus is either wholly or partially digested. During this phase, the macrophages switch to an M2 (anti-inflammatory) phenotype, cease releasing cytokines and initiate the production of healing factors such as IL-10 and TGF-beta.
- Fibroblasts, whether attracted (chemotaxis), recruited (mesenchymal stem cells) or transdifferentiated (cells from the annulus or nucleus pulposus), repair the damaged area and sequester any undigested herniated fragments by depositing connective tissue (types I and III collagen) at the site.
From a biochemical standpoint, this process deactivates the herniated tissue, rendering it inert.4
Physiology of the injury
In order to initiate the analysis of a healthy disc, it is necessary to consider not only the absence of innervation or vascularization, but also the immune system exposure of the cells that constitute the relative nucleus pulposus.5 This condition is facilitated by CSPG-type aggregate chains (Chondroitin sulfate proteoglycans) that:
- It has been demonstrated that the generation of high hydrostatic pressure is sufficient to physically prevent the growth of blood vessels.
- It has been established that these structures act as a barrier, preventing the penetration of nerves into the laminae, with the exception of the outermost one. This is reached by branches of the sinuvertebral nerve, nerves derived from the ventral branches of the spinal nerves and nerves derived from grey communicating branches. The function of these nerves is predominantly mechanoreceptor.
- It has been demonstrated that there is a considerable capacity to inhibit neuronal growth and functional neural recovery.
The depletion of aggrecan and the granulation of connective tissue result in a reduction in hydrostatic pressure (loss of hydrophilic properties), causing the disc to thin and lose its mechanical properties. In this phase, the following increase is observed:
The present study has revealed that the exposure of the cells that constitute the nucleus pulposus to an autoimmune reaction is significant. However, the data relating to the presence of natural killer cells (indicators of the presence of unrecognised material to be phagocytized) are significantly low.6
The presence of lymphocytes and macrophages at the site of action is pivotal in facilitating the synthesis of the extracellular matrix and the initiation of proteoglycan production.7 These natural macromolecules possess the capacity to restore cellular function and intensify the metabolism of the components of the connective tissue (deposit of collagen types I and III). They play a crucial role in restoring tissue functions, its mechanical properties and its physiological appearance.
The following pro-inflammatory cytokines were detected in the sample: IL-1b, IL-8, IL-6, IL-17, TNFα, IFNγ, PGE2, nerve growth factor and substance P. The median (interquartile range) concentration of these cytokines was determined to be as follows (pg/ml): The following cytokines were measured: IL-1b (15.3 [11-40.7]), IL-8 (15.2 [10.6-19.2]), IL-6 (8.29 [6.4–61.7]), TNFα (6.07 [5.34–7.68]), IL-17 (4.51 [3.73–5.18]) and IFNγ (3.14 [2.75–4.13]).8
The production of matrix metalloproteinases (MMPs) has been observed to occur in the context of neurotropic factors (BDNF) and angiogenic factors. These enzymes have the capacity to degrade the extracellular matrix, thereby acting as a barrier to neuronal growth and preventing local axons from penetrating the disc.9,10
In the domain of clinical pathology, elevated levels of pro-inflammatory cytokines have been identified in both serum samples (gelatin-like substances composed of highly hygroscopic mucopolysaccharides) and disc tissues (structures composed externally of type I collagen and internally of type II collagen andchondrocytes) of patients afflicted with severe low back pain. 11-13 However, these findings could not be attributed to or correlated with the levels of pain recorded.14 Furthermore, no differences in cytokine levels (especially IL-6) were detected between patients with and without pain, with and without disc herniation,15 before and after discectomy or laminectomy interventions. This finding suggests that cytokines may not play a primary role in maintaining a suitable network for pain generation,16 nor in determining its intensity.17
Conclusions
Postural adaptations developed during a mechanically unhealthy life alter the regular interapophyseal relationships and determine a widening of the interface in the direction indicated by the centre of gravity of the affected vertebra. The decrease in disc thickness, the consequent degeneration of the annulus fibrosus, or the herniation of the nucleus pulposus, therefore, occur as a result of a progressive alteration of the physiological curves (paramorphisms and dysmorphisms), with a strong alteration of the loads acting on the spinal segments. In pathological processes that originate from the loss of the physiological balance between degenerative and reparative phenomena, neither the damage to the disc cartilaginous tissues (without innervation), nor the high levels of cytokines detected,18 appear to have the ability to induce pain sensations 19 or determine their intensity.20
In this context, it is important to note that clinical severity is influenced by the relationships between the sensory-discriminative (identifies and relates to receptor activity), affective-motivational (defines the emotional impact resulting from lived experience), and cognitive-social (interprets sensation based on memories, expectations, and beliefs) dimensions. Consequently, the contribution of isolated anatomical and pathological alterations, such as degeneration of the annulus fibrosus, herniation of the nucleus pulposus, and inflammatory markers, is very limited and has marginal predictive and diagnostic value in nonspecific conditions. Conversely, the mechanical-structural component offers a more robust interpretative model, without assuming an exclusive or dominant etiological role.21
Conflict of interests
The authors declare that this article was written without any conflicts of interest.
Open Access License. This article is distributed under the terms of the Creative Commons Attribution_Non Commercial 4.0 International License (CC BY-NC 4.0).
Published
24th September 2026
Bibliografia
1) Burton AK. European guidelines for prevention in low back pain. COST B13 Working Group. 2004: 1-53.
2) Brinjikji W, Luetmer PH, Comstock B et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol 2015; 36(4):811-6. doi: 10.3174/ajnr.A4173. Epub 2014 Nov 27. PMID: 25430861; PMCID: PMC4464797.
3) Foster N, Anema J, Cherkin D et al. Prevention and treatment of low back pain: evidence, challenges, and promising directions, The Lancet 2018; 391, 2368-2383.
4) Ye F, Lyu F.-J, Wang H et al. The involvement of immune system in intervertebral disc herniation and degeneration. JOR Spine 2022; 5(1) e1196. https://doi.org/10.1002/jsp2.1196.
5) Sun Z, Liu B, Luo ZJ. The immune privilege of the intervertebral disc: implications for intervertebral disc degeneration treatment. Int J Med Sci 2020;17:685‐692.
6) Sato N, Kikuchi S, Sato K. Quantifying the stress induced by distress in patients with lumbar disc herniation in terms of natural killer cell activity measurements: chromium release assay versus multiparameter flow cytometric assay. Spine (Phila Pa1976). 2002;27:2095‐2100.
7) Rime B, Maigne JY. Evolution naturelle des hernies discales. Revue de Medécine Vertébrale 2004; 14.
8) Samuelly-Leichtag G, Eisenberg E, Zohar Y. Mechanism underlying painful radiculopathy in patients with lumbar disc herniation. European Journal of Pain 2022; 26:1269–1281. https://doi.org/10.1002/ejp.1947.
9) Melrose J, Roberts S, Smith S, et al. Increased nerve and blood vessel ingrowth associated with proteoglycan depletion in an ovine anular lesion model of experimental disc degeneration. Spine (Phila Pa 1976). 2002;27:1278‐1285.
10) Tolofari S, Richardson SM, Freemont AJ et al. Expression of semaphorin 3A and its receptors in the human intervertebral disc: potential role in regulating neural ingrowth in the degenerate intervertebral disc. Arthritis Res Ther 2010;12:R1.
11) Petersen KK, Arendt-Nielsen L, Simonsen O et al. Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement. Pain 2015; 156(1), 55– 61. https://doi.org/10.1016/j.pain.0000000000000022.
12) Wang K, Bao JP, Yang S et al. A cohort study comparing the serum levels of pro-or anti-inflammatory cytokines in patients with lumbar radicular pain and healthy subjects. European Spine Journal 2016; 25(5): 1428–1434. https://doi.org/10.1007/s00586-015-4349-4.
13) Zu B, Pan H, Zhang X et al. Serum levels of the inflammatory cytokines in patients with lumbar radicular pain due to disc herniation. Asian Spine Journal, 10(5), 843– 849. https://doi.org/10.4184/asj.2016.10.5.843.
14) Samuelly-Leichtag G, Eisenberg E, Zohar Y. Mechanism underlying painful radiculopathy in patients with lumbar disc herniation. European Journal of Pain; 26: 1269–1281. https://doi.org/10.1002/ejp.1947.
15) Schistad EI, Espeland A, Pedersen L et al. Association between baseline IL-6 and 1-year recovery in lumbar radicular pain. European Journal of Pain (London, England) 2014; 18(10), 1394–1401. https://doi.org/10.1002/j.1532-2149.2014.502.
16) Andrade P, Hoogland G, Garcia MA et al. Elevated IL-1β and IL-6 levels in lumbar herniated discs in patients with sciatic pain. European Spine Journal 2013; 22(4), 714– 720. https://doi.org/10.1007/s00586-012-2502-x.
17) Samuelly-Leichtag G, Eisenberg, E, Zohar Y et al. Mechanism underlying painful radiculopathy in patients with lumbar disc herniation. European Journal of Pain 2022; 26, 1269–1281. https://doi.org/10.1002/ejp.1947.
18) Peng Y, Lv FJ. Symptomatic versus asymptomatic intervertebral disc degeneration: is inflammation the key? Crit Rev Eukaryot Gene Expr. 2015;25:13‐21.
19) Andrade P, Hoogland G, Garcia MA et al. Elevated IL-1β and IL-6 levels in lumbar herniated discs in patients with sciatic pain. European Spine Journal 2013; 22(4), 714– 720. https://doi.org/10.1007/s00586-012-2502-x.
20) Samuelly-Leichtag G, Eisenberg E, Zohar Y et al. Mechanism underlying painful radiculopathy in patients with lumbar disc herniation. European Journal of Pain 2022; 26, 1269–1281. https://doi.org/10.1002/ejp.1947.
21) Foster N, Anema J, Cherkin D et al. Prevention and treatment of low back pain: evidence, challenges, and promising directions, The Lancet, 2018; 391, 2368-2383.