Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats

Abstract

Herniation of the nucleus pulposus (NP) from lumbar intervertebral discs commonly results in radiculopathic pain and paresthesia (sciatica). While traditionally considered the result of mechanical compression of the dorsal root ganglion (DRG) and/or spinal nerve root, recent studies implicate pro-inflammatory mediators released from or evoked by NP, a possibility that was presently investigated. Single-unit recordings were made from L5 wide dynamic range dorsal horn neurons in pentobarbital-anesthetized rats. Autologous NP was harvested from a coccygeal disc and placed onto the exposed L5 DRG. A control group had subcutaneous adipose tissue or saline placed similarly. To test involvement of tumor necrosis factor-alpha (TNF-alpha), a third group received autologous NP plus local soluble TNF-alpha receptor type 1 (0.013 microg) which binds TNF-alpha to prevent its action. In each group, neuronal responses to graded heat (38-50 degrees C) and mechanical (von Frey filaments 4-76 g) stimuli were recorded prior to and at three successive hourly intervals following each treatment. Responses to noxious heat and mechanical stimuli were significantly enhanced 1 h post-NP and remained elevated thereafter. Thermally and mechanically evoked responses were not significantly affected in control rats or those treated with NP + soluble TNF-alpha receptor type 1. These results indicate that sensitization of nociceptive spinal neuronal responses develops quickly following exposure of the DRG to NP, and that TNF-alpha is involved. This electrophysiological model of herniated NP may prove useful in further characterizing the role of inflammatory mediators in hyperalgesia and allodynia resulting from lumbar disc herniation.

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

“…These changes in ion flux could be responsible for the acute behavioral hypersensitivity produced in the absence of immediate axonal degeneration. Together with the results from this study, such findings suggest that immediate behavioral hypersensitivity in this model of transient compression may result from an immediate release of proinflammatory cytokines by resident cells, or via altered primary afferent electrical activity that occurs prior to the neuronal degeneration or macrophage infiltration observed later at day 7 (Figure 3 & Figure 5) (Waxman et al, 1999;Boucher et al, 2000;Cuellar et al, 2004;Sommer and Kress, 2004;Iwata et al, 2004;Xie et al, 2006;Kirita et al, 2007). Further studies are required to determine the role of these inflammatory mediators as a function of nerve root compression mechanics.…”

“…Vasogenic edema in the nerve root has been shown to increase within 1 hour for compression loads greater than 15gf (147mN) in a canine model of lumbar radiculopathy (Kobayashi et al, 1993;Kobayashi and Yoshizawa, 2002); although those canine studies did not investigate behavioral outcomes, the enhanced extravasation of protein tracers from radicular capillaries following nerve root compression suggests a potential route for circulating inflammatory cells to infiltrate the endoneurial space. Moreover, inflammatory cytokines, such as TNF-α and IL-1β, can increase in the DRG and spinal cord as early as within the first 24 hours in models of neuropathic and inflammatory pain (Cuellar et al, 2004;Sommer and Kress, 2004;Xie et al, 2006). Since macrophage infiltration was not observed at day 1 (Table 1), if the onset of nerve root-mediated behavioral hypersensitivity involves local cytokines, the source of these cytokines may be the resident neurons and/or glial cells already present at the site of injury.…”

Chemical and mechanical nerve root insults induce differential behavioral sensitivity and glial activation that are enhanced in combination

“…Although contralateral allodynia has been induced by mechanical insults in the absence of any chemical loading, those studies implemented either ligation of multiple nerve roots or the spinal nerve, imposing a more severe sustained mechanical compression and one which may induce either a more robust, or continuous, barrage to the nociceptive cascades (Tabo et al, 1999;Araujo et al, 2003). While we did not specifically probe electrophysiologic properties of spinal interneurons, neuronal sensitization in the spinal cord can be initiated by increased neurotransmitter release, inflammatory cytokines, or directly by glial cells (Schiefer et al, 1999;Tabo et al, 1999;Cuellar et al, 2004;Inoue, 2005;Tsuda et al, 2005). Ipsilateral astrocytic activation was present at day 7 following compression and was further increased for the combined injury ( Figs.…”

Contribution of Inflammation to Chronic Pain Triggered by Nerve Injury

“…The role of pro-inflammatory cytokines IL-6, IL-1 and TNF- has been extensively studied. Blockers of these cytokines have been shown to reduce neuroinflammatory responses (Gomez-Nicola et al, 2008;Kiguchi et al, 2010) reduce neuronal hyperexcitability (Milligan et al, 2001) and block pain in animal models of neuropathy (Cuellar et al, 2004).…”