Pharmacological Inhibition of Tumor Necrosis Factor May Reduce Pain Behavior Changes Induced by Experimental Disc Puncture in the Rat

Nakamae, Toshio; Ochi, Mitsuo; Olmarker, Kjell

doi:10.1097/brs.0b013e3181d8bef3

Cited by 27 publications

(22 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Infliximab has been used at a dose 5mg/kg epidurally in humans with limited effect [23, 24]. However, infliximab has also been used at a dose of 0.5 – 5 mg/kg systemically and 5 mg/kg intradiscally in rats with more promising results [28]. Scaling intradiscal dosing from rats to humans is not a linear relationship based on body weight due to differences in transport and cell density [39].…”

Section: Discussionmentioning

confidence: 99%

“…In another study, epidural delivery of anti-TNFα was less effective than epidural steroidal treatments in improving pain in a multicenter trial, although no statistically significant differences were detected and the authors noted that it was impossible to conclude whether a TNFα inhibitor delivered for longer times or at higher doses could have been more effective [27]. In an in vivo experimental study in rats, lumbar disc puncture through the AF induced pain associated behavioral changes, which were decreased with local infliximab delivery to the IVD [28]. Systemic drug administration for back pain is often not effective, which is likely due to the poor transport environment inhibiting delivery of drugs into the IVDs or due to rapid absorption from the epidural space [4, 16, 29].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug

et al. 2015

View full text Add to dashboard Cite

Background context Intervertebral discs (IVD) are attractive targets for local drug delivery because they are avascular structures with limited transport. Painful IVDs are in a chronic inflammatory state. While anti-inflammatories show poor performance in clinical trials their efficacy treating IVD cells suggests that sustained, local drug delivery directly to painful IVDs may be beneficial. Purpose To determine if genipin crosslinked fibrin (FibGen) with collagen type I hollow spheres (CHS) can serve as a drug delivery carrier for the anti-TNFα drug, infliximab. Infliximab was chosen as a model drug because of the known role of TNFα in increasing downstream production of several pro-inflammatory cytokines and pain mediators. FibGen was used as drug carrier because it is adhesive injectable, slowly degrading hydrogel with potential to seal annulus fibrosus (AF) defects. CHS allow simple and non-damaging drug loading and could act as a drug reservoir to improve sustained delivery. Study Design/Setting Biomaterials and human AF cell culture study to determine drug release kinetics and efficacy. Methods Infliximab was delivered at low and high concentrations using FibGen with and without CHS. Gels were analyzed for structure, drug release kinetics, and efficacy treating human AF cells following release. This work was funded by grants from the NIAMS/NIH (R01 AR057397), AO Foundation, and from the Icahn School of Medicine at Mount Sinai. Results Fibrin showed rapid infliximab drug release but degraded quickly. CHS alone showed a sustained release profile but the small spheres may not remain in a degenerated IVD with fissures. FibGen showed steady and low levels of infliximab release that was increased when loaded with higher drug concentrations. Infliximab was bound in CHS when delivered within FibGen and was only released following enzymatic degradation. The infliximab released over 20 days retained its bioactivity as confirmed by the sustained reduction of IL-1β, IL-6, IL-8, and TNFα concentrations produced by AF cells. Conclusions Direct mixing of infliximab into FibGen was the simplest drug loading protocol capable of sustained release. Results show feasibility of using drug-loaded FibGen for delivery of infliximab and, in the context with the literature, show potential to seal AF defects and partially restore IVD biomechanics. Future investigations are required to determine if drug-loaded FibGen can effectively deliver drugs, seal AF defects, and promote IVD repair or prevent further IVD degeneration in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug

et al. 2015

View full text Add to dashboard Cite

show abstract

“…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]. These studies have provided a group of measurement techniques for pain associated with spine pathology in rats; however, there remains a gap in the investigation of discogenic pain, or disc degeneration-associated pain in the absence of demonstrable herniation and radicular pain.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

“…TNF-α can stimulate the production of pro-inflammatory cytokines, matrix degrading enzymes, and pain mediators (Millward-Sadler et al, 2009; Purmessur et al, 2013; Seguin et al, 2005; Weiler et al, 2005). TNF-α is also implicated in painful spine conditions with infliximab and other TNF-α inhibitors showing improved pain and behavioral responses in clinical trials and animal studies (Allen et al, 2011; Likhitpanichkul et al, 2015; Risbud and Shapiro, 2014; Shamji et al, 2010; Nakamae et al, 2011). However, clinical trial results using infliximab are mixed possibly due to inadequate dosing or delivery (Risbud and Shapiro, 2014) highlighting a need for improved knowledge of how TNF-α affects IVD cells.…”

Section: Introductionmentioning

confidence: 99%

Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

Likhitpanichkul

Torre

Gruen

et al. 2016

Journal of Biomechanics

View full text Add to dashboard Cite

During intervertebral disc (IVD) injury and degeneration, annulus fibrosus (AF) cells experience large mechanical strains in a pro-inflammatory milieu. We hypothesized that TNF-α, an initiator of IVD inflammation, modifies AF cell mechanobiology via cytoskeletal changes, and interacts with mechanical strain to enhance pro-inflammatory cytokine production. Human AF cells (N=5, Thompson grades 2–4) were stretched uniaxially on collagen-I coated chambers to 0%, 5% (physiological) or 15% (pathologic) strains at 0.5 Hz for 24 hours under hypoxic conditions with or without TNF-α (10 ng/mL). AF cells were treated with anti-TNF-α and anti-IL-6. ELISA assessed IL-1β, IL-6, and IL-8 production and immunocytochemistry measured F-actin, vinculin and α-tubulin in AF cells. TNF-α significantly increased AF cell proinflammatory cytokine production compared to basal conditions (IL-1β:2.0±1.4 to 84.0±77.3, IL-6:10.6±9.9 to 280.9±214.1, IL-8:23.9±26.0 to 5125.1±4170.8 pg/ml for basal and TNF-α treatment, respectively) as expected, but mechanical strain did not. Pathologic strain in combination with TNF-α increased IL-1β, and IL-8 but not IL-6 production of AF cells. TNF-α treatment altered F-actin and α-tubulin in AF cells, suggestive of altered cytoskeletal stiffness. Anti-TNF-α (infliximab) significantly inhibited pro-inflammatory cytokine production while anti-IL-6 (atlizumab) did not. In conclusion, TNF-α altered AF cell mechanobiology with cytoskeletal remodeling that potentially sensitized AF cells to mechanical strain and increased TNF-α-induced pro-inflammatory cytokine production. Results suggest an interaction between TNF-α and mechanical strain and future mechanistic studies are required to validate these observations.

show abstract

Pharmacological Inhibition of Tumor Necrosis Factor May Reduce Pain Behavior Changes Induced by Experimental Disc Puncture in the Rat

Abstract: The present study showed that TNF inhibition induced a marked reduction of wet dog shakes. It is not fully understood if wet-dog shakes may relate to LBP, but in view of recent clinical findings one may consider clinical studies of TNF inhibition for the treatment of LBP.

Cited by 27 publications

References 53 publications

Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug

Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug

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

Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

Contact Info

Product

Resources

About