Complete Freund’s Adjuvant-Induced Intervertebral Discitis as an Animal Model for Discogenic Low Back Pain

Lee, Min; Kim, Byung Jo; Lim, Eic Ju; Back, Seung Keun; Lee, Ju Han; Yu, Sung Wook; Hong, Sung; Kim, Joo Han; Lee, Sang‐Heon; Jung, Woon Won; Sul, Donggeun; Na, Heung Sik

doi:10.1213/ane.0b013e3181b31f39

Cited by 39 publications

(49 citation statements)

References 32 publications

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“…These findings suggested that the disc inflammatory state might play a more important role in the level of pain. The association between pro-inflammatory cytokines and discogenic pain was previously demonstrated using an intradiscal injection of complete Freund adjucant, a pro-inflammation mediator, to induce discitis [18]. However, this is the first study to investigate the association between TNFα, a natural pro-inflammatory cytokine thought to be an initiator of disc degeneration, and painful behavior in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…Hindpaw mechanical hyperalgesia is a measurement of pain sensitivity using a series of calibrated von Frey filaments corresponding to forces between 0.4 and 26.0 g (Stoelting, Wood Dale, IL, USA) [18,19]. After 20 minutes acclimations, calibrated filaments were applied in ascending order from 0.4 g to 26.0 g until a positive response was elicited.…”

Section: Methodsmentioning

confidence: 99%

“…Rat models have been widely used for studying discogenic pain because the pain associated with disc injury can be assessed with various measurement techniques [18–29]. Most animal studies on disc degeneration and pain have investigated the pathophysiology of disc herniation and radicular pain following posterolateral annular puncture with herniated NP [23,30] or nerve root compression with NP materials from caudal discs [26–28,31].…”

Section: Introductionmentioning

confidence: 99%

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Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

et al. 2016

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BACKGROUND CONTEXT Painful intervertebral disc degeneration is extremely common and costly. Effective treatments are lacking because the nature of discogenic pain is complex with limited capacity to distinguish painful conditions from age-related changes in the spine. Hypothesized sources of discogenic pain include chronic inflammation, neurovascular ingrowth, and structural disruption. PURPOSE This study aimed to investigate inflammation, pro-neurovascular growth factors, and structural disruption as sources of painful disc degeneration STUDY DESIGN/SETTING This study used an in vivo study to address these hypothesized mechanisms with anterior intradiscal injections of tumor necrosis factor-alpha (TNFα), pro-neurovascular growth factors: nerve growth factor and vascular endothelial growth factor (NGF and VEGF), and saline with additional sham surgery and naïve controls. Depth of annular puncture was also evaluated for its effects on structural and painful degeneration. METHODS Rat lumbar discs were punctured (shallow or deeper puncture) and intradiscally injected with saline, TNFα, or NGF and VEGF. Structural disc degeneration was assessed using X-ray, magnetic resonance imaging (MRI), and histology. The rat painful condition was evaluated using Von Frey hyperalgesia measurements, and substance P immunostaining in dorsal root ganglion (DRG) was performed to determine the source of pain. RESULTS Saline injection increased painful responses with degenerative changes in disc height, MRI intensity, and morphologies of disc structure and cell. TNFα and NGF/VEGF accelerated painful behavior, and TNFα-injected animals had increased substance P in DRGs. Deeper punctures led to more severe disc degeneration. Multiple regression analysis showed that the painful behavior was correlated with disc height loss. CONCLUSIONS We concluded that rate and severity of structural disc degeneration was associated with the amount of annular disruption and puncture depth. The painful behavior was associated with disc height loss and discal inflammatory state, whereas pro-inflammatory cytokines might play a more important role in the level of pain, which might have resulted from enhanced DRG sensitization. These in vivo painful disc degeneration models with different severities of structural changes may be useful for investigating discogenic pain mechanisms and for screening therapies, although interpretations must note the differences between all surgically induced animal models and the human condition.

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

et al. 2016

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“…A significantly decreased pain threshold—as measured by vocal responses to microfilaments applied to the spinous process—was found up to 7 weeks after puncturing the L5/6 IVD ventrolaterally with a 26-gauge needle and injection of 10 μL complete Freund’s adjuvant (CFA) with an anterior approach in a rat. 108 Our group has developed a model of painful IVD degeneration wherein an anterior IVD puncture with TNF-α injection induces a decreased mechanical hindpaw withdrawal threshold. 44 We believe the use of TNF-α is more physiologically relevant than CFA, as TNF-α has been extensively implicated in IVD degeneration and may better lend itself to understanding the underlying pathophysiology of IVD degeneration–related pain in an animal model.…”

Section: Existing Models Of Painful Ivd Degenerationmentioning

confidence: 99%

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

Mosley

Evashwick‐Rogler

Lai

et al. 2017

Annals of the New York Academy of Sciences

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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, this review describes the different ways to classify pain in human patients and in 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.

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“…The ingrowth of nociceptive neural fiber into deeper parts of the degenerative disc is considered as one of the most widely accepted pathomechanisms related to chronic discogenic pain (87). As the IVDD proceeds, disc inflammation may promote axonal growth of afferent fibers from the dorsal root ganglia (DRG) (88) to innervate the disc by secreting proinflammatory mediators.…”

Section: Applications Of C60 and Derivatives In Orthopaedic Researchmentioning

confidence: 99%

The applications of buckminsterfullerene C₆₀and derivatives in orthopaedic research

Liu

Cui

et al. 2014

Connective Tissue Research

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Buckminsterfullerene C60 and derivatives have been extensively explored in biomedical research due to their unique structure and unparalleled physicochemical properties. C60 is characterized as a “free radical sponge” with an anti-oxidant efficacy several hundred-fold higher than conventional anti-oxidants. Also, the C60 core has a strong electron-attracting ability and numerous functional compounds with widely different properties can be added to this fullerene cage. This review focused on the applications of C60 and derivatives in orthopaedic research, such as the treatment of cartilage degeneration, bone destruction, intervertebral disc degeneration (IVDD), vertebral bone marrow disorder, radiculopathy, etc., as well as their toxicity in vitro and in vivo. We suggest that C60 and derivatives, especially the C60 cores coupled with functional groups presenting new biological and pharmacological activities, are advantageous in orthopaedic research and will be promising in clinical performance for musculoskeletal disorders treatment; however, the pharmacokinetics and toxicology of these agents as local/systemic administration need to be carefully determined.

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Complete Freund’s Adjuvant-Induced Intervertebral Discitis as an Animal Model for Discogenic Low Back Pain

Cited by 39 publications

References 32 publications

Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

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

The applications of buckminsterfullerene C₆₀and derivatives in orthopaedic research

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Complete Freund’s Adjuvant-Induced Intervertebral Discitis as an Animal Model for Discogenic Low Back Pain

Cited by 39 publications

References 32 publications

Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo

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

The applications of buckminsterfullerene C60and derivatives in orthopaedic research

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Product

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The applications of buckminsterfullerene C₆₀and derivatives in orthopaedic research