INTRODUCTION
Low back pain is the most common musculoskeletal disorder affecting adults, with a prevalence of 84% and a chronic disability of 10%[1]. It is one of the most important medical and social problems globally. Any neurally innervated structure of the lumbar spine, such as muscles, ligaments, vertebrae, facet joints, and discs, may be a source of low back pain. Multiple studies have shown that low back pain caused by lumbar intervertebral disc degeneration (IVDD), also known as discogenic low back pain, is the most common type of low back pain and one of the leading causes of disability[1]. Recently, the National Center for Health Statistics has approved and published specific International Classification of Diseases, 10th Revision, Clinical Modification codes for lumbosacral discogenic pain associated with degenerative disc disease[2]. These codes came into effect on October 1, 2024[3]. Given the high incidence of discogenic back pain, appropriate and accurate diagnosis and classification of patients with discogenic low back pain is an important step forward in spinal care. IVD consists of three distinct components: a gelatinous core known as the nucleus pulposus; the annulus fibrosus, a fibrocartilage that transversely restricts the nucleus pulposus; and two cartilage endplates, which are thin, hyaline cartilage layers covering the cranial and caudal ends of the nucleus pulposus and inner annulus[4]. Multiple studies have linked IVDD to various risk factors, such as aging, trauma, infection, smoking, vibration exposure, and genetic inheritance[5,6]. However, the exact mechanisms underlying IVDD and its progression to discogenic pain remain unclear.
INNERVATION OF IVD
A healthy IVD is the largest avascular and nerve-free tissue in adults, with nerves and blood vessels located only in the outermost annulus fibrosus and bony endplates[7]. The innervation of IVD is very complex. Nerve fibers that innervate a lumbar disc originate from multiple dorsal root ganglion (DRG) neurons, and each neuron in a DRG can innervate multiple discs. The sensory nerve fibers innervating the lumbar IVD are mainly composed of small myelinated A-delta fibers and unmyelinated C fibers. These tiny fibers express the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), which are nociceptors associated with inflammatory pain. They are nerve growth factor (NGF)-dependent and express high-affinity tyrosine kinase A receptors, indicating their central role in conducting nociceptive stimuli from painful intervertebral discs[8].
PATHOPHYSIOLOGY OF IVDD
IVDD usually refers to a decrease in signal intensity on magnetic resonance imaging (MRI) T2-weighted images, known as a “black disc.” MRI can differentiate IVDD, but it does not help to distinguish pathologically painful discs from physiologically aged ones. Age-related changes can affect all intervertebral discs, including decreased cell viability, impaired metabolite transport, and reduced proteoglycan synthesis. These changes lead to a smaller nucleus pulposus volume and increased compressive stress on the outer annulus fibrosus. Aged discs, with decreased water content, appear hypointense on T2-weighted MR images, but this does not necessarily correlate with low back pain[9]. Painful degenerative discs are always structurally ruptured, whether in the annulus or endplate[10-13]. However, not all intervertebral discs rupture. Lower lumbar intervertebral discs, especially the posterior part of their annulus fibrosus, are the most common sites affected, likely because they bear the greatest loads and have a weaker structure[14,15]. Some of the risk factors mentioned earlier, such as smoking, repetitive mechanical stress, and genetic inheritance, accelerate the aging of intervertebral discs, making them more fragile and prone to rupture during daily activities[14]. Histologically, painful degenerative discs due to annular tears are characterized by the formation of vascularized granulation tissue extending into the nucleus pulposus along the tear of the annulus fibrosus, accompanied by extensive nociceptive nerve distribution[11,12]. Animal models of disc degeneration have revealed that annular or endplate injury inevitably leads to degenerative changes throughout the disc[16-19]. Lumbar disc degeneration has two phenotypes: annulus-driven and endplate-driven. The former is associated with annulus tears and is more common in the lower lumbar spine, with a low heritability. In contrast, endplate-driven degeneration is associated with endplate defects and is common in the thoracolumbar spine, with a high heritability[10].
Annular tear is synonymous with fissure, but the term “tear” often implies a traumatic cause[20]. Biomechanics studies have shown that the outer layer of the annulus fibrosus bears the highest tensile stress and is most susceptible to injury[14,16]. There are three types of annular tears: circumferential tear, also known as delamination; annular rim tear; and radial tear[10,16]. Histological studies of annular tears in painful discs have revealed the entire process of annulus fibrosus healing, including inflammatory cell infiltration, granulation tissue formation, and tissue remodeling, suggesting that the annulus fibrosus is actually torn and undergoes an active healing process[11]. However, the healing process in disc tissue differs from that of normal tissues. In most tissues, healing progresses from deep to superficial layers, while in the intervertebral disc, the repair process moves from the vascularized outer layer of the annulus to the inner layer along the tear or injury. If the tear occurs in the inner layers of the annulus or nucleus pulposus, the healing process is not initiated[11]. Healing of the torn annulus fibrosus is extremely difficult, possibly not only because a sparse cell population is unable to break down large bundles of collagen fibers from the annulus and replace them with new bundles, but also because of insufficient blood supply[11]. Only low back pain caused by radial tears can be clinically confirmed, as these tears must reach the outermost or superficial layer of the annulus fibrosus[11,12], where nociceptive innervation is present. Annular rim tears may also cause low back pain, but clinical confirmation is difficult. T2-weighted MR images may show a high signal intensity zone, indicative of these tears[21]. Animal models involving scalpel cuts to the outer annulus have shown that the incision was filled with granulation tissue, while the disc underwent progressive degeneration characterized by the development of circumferential and radial tears[16]. Physically, when a part of an intervertebral disc is damaged, the load-bearing capacity of its adjacent tissues increases, leading to the spread of damage. Biologically, abnormal load can reduce the ability of intervertebral disc cells to synthesize proteoglycans[9].
The mechanisms by which IVD injury induces IVDD and subsequent discogenic back pain remain poorly understood. Studies have shown that discogenic back pain is closely related to the ingrowth of nerves and blood vessels[1,5,6,11,12]. The annular tear provides a low-pressure microenvironment, allowing for focal proteoglycan loss, leaving behind a matrix conducive to nerve and vascular ingrowth, possibly extending as far as the nucleus pulposus[22]. Studies have shown that vascular and nerve ingrowth is always located in ruptured and proteoglycan-depleted annulus[23]. Similarly, vertebral endplate damage causes blood vessels and nerves to grow vertically into the decompressed nucleus pulposus, whereas intact cartilage endplates act as a barrier and prevent such growth[24]. Histopathological studies have shown that endplates with pathological changes, such as structural defects or endplate lesions, have higher innervation densities compared to normal endplates[25]. Furthermore, the severity of endplate lesions is related to the severity of back pain as well as IVDD[26].
Inflammation is a natural physiological response to tissue injury, and the intervertebral disc is no exception. Painful disc degeneration is a consequence of locally activated inflammation following disc injury[11,13]. Animal model studies have shown that annulus fibrosus injury leads to increased production of proinflammatory molecules, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and NGF[27]. These models also exhibited behaviors indicative of back pain, such as increased mechanical sensitivity, decreased withdrawal threshold, and reduced walking distance[17,19]. In addition, increased levels of inflammatory cytokines TNF-α, IL-6, and IL-8 and matrix metalloproteinases (MMP)-3, MMP-10, and MMP-13 have been observed in painful degenerative discs[28]. These increases are attributed to the disc injury rather than being the cause of disc degeneration. Logically, saying that cytokines and matrix-degrading enzymes cause disc degeneration is like blaming soldiers for war, purely “putting the cart before the horse”[9,14]. The sensation of acute back pain following disc injury may precede or coincide with inflammation. Pain plays an important physiological role in inflammation, serving as a warning of abnormal tissue damage[29]. At present, it remains unclear whether pain, inflammation, or a combination of both acts as a trigger event that leads to IVDD. One of the key mechanisms of progressive disc degeneration induced by injury may be immune cell infiltration[1,11]. Various immune cells have been found in injured and painful discs. Invasive immune cells such as macrophages, mast cells, and lymphocytes produce cytokines and chemokines, which not only recruit more immune cells to the injured disc but also upregulate the expression of matrix-degrading enzymes[5].
ROLE OF NEUROGENIC INFLAMMATION IN IVDD AND DISCOGENIC PAIN
Normal disc cells (including nucleus pulposus and annulus fibrosus cells) express low levels of SP and CGRP and their receptors. In an inflammatory state, cultured disc cells can synthesize more CGRP and SP. The expression levels of CGRP and SP are higher in painful discs in humans compared to normal control discs, suggesting that these neuropeptides are key mediators in the development of painful disc degeneration[28,30,31]. Neuropeptides such as SP and CGRP can regulate the activity of immune cells through their respective receptors, which in turn lead to further upregulation of inflammation and nociception[32]. These neuropeptides are also potent mediators of pain and inflammation, contributing to both peripheral and central sensitization associated with inflammatory pain. In addition, the proximity of the afferent nerve endings to the disc cells suggests that these cells are the prime targets for SP and CGRP. These neuropeptides stimulate cytokine production in disc cells, and the chemicals released by disc cells may alter the excitability of afferent nerves. Therefore, SP and CGRP may act synergistically on disc cells in an autocrine or paracrine manner and may be involved in a “crosstalk” between disc cells and neurons, providing a potential mechanism for the transmission of painful disc stimuli[33].
A recent study found that disc injury increases the production of not only inflammatory cytokines such as IL-1β and IL-6 and the neurotrophin NGF but also neuropeptides SP and CGRP. Moreover, these cytokines and neuropeptides showed a synchronous and comparable increase in adjacent healthy discs[33]. As in vitro experiments have shown that SP and CGRP promote the expression of inflammatory factors in disc cells in a dose-dependent manner, the study suggests that the increase of inflammatory cytokines after disc injury is driven by neurogenic inflammation[33]. The term “neurogenic inflammation” is now widely used to describe the mechanism by which sensory nerves cause inflammation. As previously mentioned, there is nociceptive innervation in the outer layer of the disc. Nociceptive signals are generated by puncturing the annulus (mechanical stimulus) with a needle and are transmitted to multiple DRG neurons. The activated DRG neurons produce neuropeptides SP and CGRP, which are transported by fast axonal transport to injured and adjacent healthy discs to produce neurogenic inflammation[32]. At the same time, these neuropeptides are also transported to the dorsal horn of the spinal cord, which not only transmits low back pain signals to the central nervous system, but also causes spinal cord sensitization. Animal models of disc injury have shown a significant and sustained increase in SP expression in the dorsal horn of the spinal cord, suggesting activation of nociceptive A-delta and C fibers and the development of central sensitization[18,19,34].
SP and CGRP can induce the overexpression of NGF[35]. The upregulation of NGF may lead to pain hypersensitivity, allodynia, and chronic persistent pain sensation[36]. On the contrary, NGF is associated with the upregulation and promotion of CGRP and SP expression in DRG neurons[37]. In addition, NGF is associated with the ingrowth of nerve fibers in painful discs, playing a key role in the occurrence and development of neurogenic inflammation and discogenic low back pain[1,5]. Direct evidence supporting this mechanism is that inhibition of tyrosine kinase A, a high-affinity receptor for NGF, leads to a significant decrease in inflammatory cytokine and neuropeptide levels in injured and adjacent healthy discs[33]. Thus, extensive basic and clinical research findings indicate that annulus fibrosus or endplate injury initiates painful disc progressive degeneration. Disc injury (annular tear or endplate damage) activates the nociceptors located in the outer annulus or bony endplate by direct irritation, causing acute nociceptive pain. Simultaneously, the injured site initiates an inflammatory repair response, releasing inflammation mediators such as histamine, serotonin, prostaglandin E2, protons, etc., which bind to their respective receptors or ion channels located in nerve endings and activate nociceptors that cause inflammatory pain. Activated nociceptors promote the synthesis of neuropeptides SP and CGRP in DRG neurons. These neuropeptides are transported to the injured disc by rapid axonal transport and act as pro-inflammatory molecules, promoting the production of an “inflammatory soup” by inducing vasodilatation and plasma extravasation as well as by promoting the release of chemical mediators from disc cells, infiltrating immune cells, and vascular tissue[36,38]. Thus, the nervous system communicates with disc cells and immune cells through neuropeptides involved in disc neurogenic inflammation, resulting in progressive disc degeneration. In addition, owing to the inadequate blood supply to the disc tissue and its complex structure, the wound repair process is impaired, leading to chronic inflammation[11,39]. Persistent inflammation causes peripheral and central sensitization, leading to chronic discogenic back pain. Therefore, pain and inflammation work together to form a positive two-way feedback loop, leading to progressive disc degeneration and chronic persistent back pain.
CONCLUSION
Disc injury elicits an inflammatory repair response that activates nociceptors located in the outer annulus fibrosus or bony endplates. This activation leads to the release of neuropeptides, such as SP and CGRP, which in turn cause neurogenic inflammation of the disc. Owing to the lack of blood supply in the disc and its complex structure, the healing process is impaired, leading to prolonged inflammation, progressive disc degeneration, and chronic discogenic pain. In the future, pharmacological interventions targeting IVDD-related neurogenic inflammation, such as blocking the effects of SP or CGRP with neutralizing antibodies or inhibitors, may provide a novel and effective strategy for the clinical management of discogenic pain.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single-blind
Specialty type: Orthopedics
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Chen XS S-Editor: Liu H L-Editor: Filipodia P-Editor: Zhao YQ
