Dorsal horn DCC amplification loop induced by endplate osteoclasts generates chronic nociplastic low back pain in male mice, 2026, Pan et al.

[SNT Gatchaman]

Dorsal horn DCC amplification loop induced by endplate osteoclasts generates chronic nociplastic low back pain in male mice

Spoiler: Authors

Pan, Dayu; Shen, Mengxi; Abatan, Elizabeth; Zheng, Jinjian; Nasser, Philip; M Laudier, Damien; Kong, Chao; Yan, Lei; Qiu, Zhaozhu; C Iatridis, James; Wan, Mei; Zheng, Junying; K Taylor, Bradley; Cao, Xu

Spine degeneration is associated with low back pain (LBP), a major cause of disability and functional decline. However, effective therapies for non-specific LBP remain limited because its underlying mechanisms are poorly understood.

Here, we show that spine degeneration induces netrin-1 secretion in porous endplates to activate DCC signaling in dorsal root ganglion (DRG) neurons in both LBP and naturally aged male mice. Conditional loss of netrin-1 in Trap+ osteoclasts, or Dcc in Avil+ DRG neurons reduced spinal hypersensitivity. Importantly, DCC activation induces Src phosphorylation and SNARE complex docking, leading to presynaptic glutamate release in the dorsal horn (DH).

Consequently, presynaptic glutamate release induces expression of both netrin-1 and DCC in DH neurons as a form of postsynaptic plasticity that initiates a positive feedback loop to amplify spinal hypersensitivity. Moreover, netrin-1/DCC expression is also amplified in the parabrachial nucleus (PBN) in the brain in both LBP and aged male mice. Thus, osteoclast-derived netrin-1 in porous endplates activates DCC-mediated hypersensitivity in DRG neurons to be further amplified in the DH neurons.

These results promote the concept of non-specific LBP as a form of nociplastic pain.

Web | DOI | PDF | Nature Communications | Open Access

 

[SNT Gatchaman]

Thread and tag for DCC.

See also —

Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome (2025)

Identification of novel reproducible combinatorial genetic risk factors for myalgic encephalomyelitis in the DecodeME patient cohort and commonalities with long COVID (2026)

The genetic architecture of fibromyalgia across 2.5 million individuals (2026)

Genome-wide association study of multisite chronic pain in UK Biobank (2019)

 

[SNT Gatchaman]

Selected quotes from introduction —

Due to the spine’s complex architecture, spinal pain can originate from multiple sources within the spinal column. LBP [Lower Back Pain] constitutes different types of pain, including nociceptive pain, nociplastic pain with amplification of nociceptive hypersensitivity in the central nervous system (CNS), and neuropathic pain.

Nociplastic pain is defined as pain arising from increased nociception without clear evidence of ongoing tissue damage or somatosensory system disease. Clinically, it is linked to augmented central pain processing and may coexist with nociceptive non-specific pain such as chronic LBP.

recent reviews of discogenic LBP emphasize that symptomatic IVD [Intervertebral disc] degeneration is characterized not only by local inflammation and neurovascular ingrowth, but also by central sensitization at the spinal and supraspinal levels, thereby overlapping with the clinical construct of nociplastic pain.

In addition, epidemiological and psychophysical studies identify a clear chronic LBP subgroup with generalized hypersensitivity and impaired descending pain modulation, supporting a central component in structurally driven conditions such as discogenic LBP. Here, we propose an endplate-driven central mechanism that may contribute to nociplastic features of LBP.

Although IVD degeneration has been associated with LBP, clinical studies find high variability and IVD degeneration in non-painful subjects.

“porous endplate” denotes thinned endplates that are filled with microscopic cavities due to osteoclast activity; they are often accompanied by ingrowth of CGRP+ sensory fibers into the endplate/subchondral region.

Notably, nerve density is significantly higher in fibrovascular endplate marrow than in morphologically normal human endplates20 . Calcitonin gene-related peptide (CGRP) is a well-established marker of nociceptive C and Aδ afferents, which are critically involved in pain transmission and neurogenic inflammation.

Netrins are a conserved family of secreted guidance cues that play essential roles in axon guidance and neural circuit formation during nervous system development. Among the netrin family members, netrin-1 functions primarily through the transmembrane receptor Deleted in Colorectal Cancer (DCC) to mediate chemoattraction of commissural axons and promote axonal growth.

Genome-wide association studies (GWAS) have identified Dcc, the receptor of netrin-1, as a prime risk gene for chronic pain. When it interacts with netrin-1, DCC serves as a chemoattractant that guides axonal growth during neurodevelopment, which is essential for the development of nociceptive topognosis in both mice and humans.

Other studies have found that Dcc is also the most extensively pleiotropic psychiatric risk gene. Netrin-1 expression in the CNS can regulate synaptic plasticity by promoting the trafficking of glutamatergic AMPARs.

 

[SNT Gatchaman]

Selected quotes from discussion —

Chronic LBP is a leading cause of medical consultations, with persistent pain at rest profoundly impairing quality of life and daily physical activity.

LBP is a typical example of non-specific pain. Here, we further investigate DCC-mediated non-specific pain mechanism. We demonstrated that netrin-1/DCC signaling is amplified in a dorsal horn as a feed-back-loop to transmit the nociplastic signal from endplate → DRG → dorsal horn → brain.

The term “nociplastic pain” was recently introduced by some in the international pain research community to categorize pain driven by central nervous system mechanisms that are distinct from peripheral nociceptive pain driven by ongoing inflammation or tissue injury and peripheral neuropathic pain driven by nerve damage. Our findings provide a mechanism of nociplastic LBP.

Specifically, 80–90% of LBP patients in the clinic are classifided as nonspecific LBP with no single pathoanatomical cause identified. Clinical studies suggest that pain arises from endplates although vertebral endplate porosity is not technically detected in clinical imaging and grading systems.

Our results show that osteoclast netrin-1 in porous endplates induces sensory innervation for nociceptive signals amplified as nociplastic LBP in the spinal cord and PBN [Parabrachial nucleus]. This persistent, centrally driven amplification is consistent with the International Association for the Study of Pain (IASP) definition of nociplastic pain.

The parabrachial nuclei are in the dorsal upper pons (Wikipedia).

Nociceptor-associated ion channels, including TRPV1 and TRPA1 ion channels, which are expressed not only peripherally but also at presynaptic terminals in the spinal dorsal horn, where they potentiate glutamatergic transmission independent of NMDA receptors.

In elderly human subjects, we observed a threefold increase in CGRP-positive nerve fiber ingrowth of endplate, which was accompanied by elevated DCC expression

Although Lu et al. reported that CGRP+ neurons can promote tissue healing through immunomodulatory interactions with neutrophils and macrophages under certain contexts, our findings suggest that netrin-1 from the vertebral endplate activates netrin-1-DCC signaling along the DRG-dorsal horn axis to induce the neuroplasticity that underlies chronic LBP. Moreover, our finding of active, self-sustained netrin-1/ DCC signaling in PBN neurons suggests that skeletal pain-induced Dcc expression may underlie the psychological comorbidities that LBP patients can experience.

 

[SNT Gatchaman]

The last sentence returns to the initial framing of a population with significant psychological issues, supported by two references, including:

Nociplastic pain: towards an understanding of prevalent pain conditions (2021)

Spoiler: Abstract

Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage.

The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems.

This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain.

It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Web | PDF | The Lancet | Paywall

That includes passages such as —

The foundation for diagnosing a nociplastic condition is a comprehensive evaluation, paying attention to the characteristics of the pain, the presence of other somatic and psychological symptoms, and physical examination to identify underlying differential diagnostic and comorbid conditions (panel 1). Historical features that point towards a nociplastic condition include a family or childhood history of pain, and prominent symptoms such as fatigue, cognitive problems, multiple environmental sensitivities, and psychological symptoms.

Panel 2: Clues in patient’s history suggestive of nociplastic pain syndrome

• Childhood and adolescent symptoms of pain (eg, headache, abdomen, or low back)
• General symptoms (eg, fatigue and cognitive problems)
• Hypersensitivity to environmental stimuli (eg, light or sound)
• Psychological symptoms (eg, anxiety or depression)
• Symptoms causing a high amount of emotional strain
• A family history of chronic pain and mental health problems
• High use of health-care services (eg, many doctor visits or investigations)
• Poor or no response to conventional analgesics (including opioids)

Earlier they stated —

Nociplastic pain represents a dynamic interplay of various mechanisms causing or amplifying pain, arising de novo or triggered by pain generator(s) that can be driven by the peripheral nervous system or the CNS, psychologically driven, or a combination.

So the evidence from this thread's paper would seem to be the former: nociplastic pain being driven by peripheral nervous system (the DRG) at the interface with the CNS (dorsal horn nuclei), a long way from higher centres, and in the wrong direction.

Associations with psychological observations could be due to: 1) patients living with uncontrolled/untreated (and medically stigmatised) pain; and 2) the association with DCC and its dual role in neural development in the CNS (cortical synapse formation) and out in peripheral nerves.

 

[Jonathan Edwards]

I have never seen any reason to think of back pain as nociplastic. It is nearly always in the L4-S1 region, which is where discs fall apart in nearly all of us. It is just a mechanical design fault. The miracle is that intervertebral discs last 80 years despite a weird mixed structure including avascular centres and rims formed from vascularised entheses.

 

[rvallee]

I don't understand much of it, but it doesn't seem to support in any way the concept of nociplastic whatever? In fact, the opposite. Especially not any of the ridiculous nonsense described in SNT's comment above.