Abstract
BackgroundPainful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor‐alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear.PurposeTreatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro‐inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro‐inflammatory cytokine expression.MethodsLumbar IVDs were punctured anteriorly and injected with TNFα, anti‐TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6‐weeks post‐surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin‐1 beta (IL‐1β) expressions were assayed.ResultsIntradiscal TNFα injection increased pain and IVD degeneration whereas anti‐TNFα alleviated pain to sham level. Multivariate step‐wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL‐1β.DiscussionThe significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.
Highlights
The findings suggested that TNFα plays an important role in the development of Intervertebral disc (IVD) degeneration-related pain; it is unclear whether inhibiting TNFα at the time of IVD injury can prevent or mitigate IVD degeneration and degeneration-related pain
This study identified multifactorial causes of painful IVD degeneration and determined a causal role for TNFα on the initiation of IVD degeneration Intradiscal % TNFα positivity Intradiscal % interleukin-1 beta positivity Normalized IVD height
IVD degeneration grade and intradiscal TNFα expression were identified as predictive factors for IVD degeneration-related pain using stepwise multivariate regression, while univariate correlation analysis further identified associations of pain with IVD height loss and intradiscal interleukin-1 beta (IL-1β) expression
Summary
Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor-alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro-inflammatory cytokine expression. 6-weeks post-surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin-1 beta (IL-1β) expressions were assayed. Pain threshold was linearly associated with IVD height loss and IL-1β. Discussion: The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. KEYWORDS axial back pain, discogenic pain, disc height, infliximab, intervertebral disc degeneration, low back pain, mechanical hyperalgesia, tumor necrosis factor-alpha
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