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Recently, it was observed that local application of nucleus pulposus may induce a characteristic reaction at the surface of the dorsal root ganglion (DRG). This change was inflammatory in nature and occurred as early as 1 day after the application of nucleus pulposus. Herniation of the nucleus pulposus was surgically induced in the L4-5 disc in rats. The L4 DRGs were resected 3, 24, and 72 h after surgery and sectioned. The sections were processed for immunohistochemistry using antisera to the macrophage marker ED1 and observed using light microscopy. The appearance of macrophages was confirmed 3, 24, and 72 h after the surgery. Macrophages were mainly distributed in the epineurial space of the DRG 3 h after disc incision and also in the endoneurial tissue 24 and 72 h after disc incision. The immunoreactivity was significantly stronger at 24 and 72 h than at 3 h in the parts of the DRG without apparent changes in the disc incision series (p < 0.01). Within the epineurium adjacent to application of nucleus pulposus, the number was significantly higher at 3 h than at 24 and 72 h (p < 0.05). We conclude that experimental disc herniation with leakage of nucleus pulposus results in macrophage recruitment to the epineurium of the DRG 3 h after disc incision and to the endoneurium 24 and 72 h after disc incision.

The route by which an epidurally applied macromolecule might reach the endoneurial space of spinal nerve roots was assessed with light and electron microscopy in a pig model established to explore the pathophysiology of disk herniation. Horseradish peroxidase (HRP) dissolved in saline was infused epidurally. Animals were sacrificed after 5 minutes (n = 5) or 30 minutes (n = 5). Two control animals received only a saline infusion and were sacrificed after 30 minutes. Nerve root specimens were collected, fixed, and exposed to the HRP substrate, 3.3'-di-amino-benzidine (DAB). The distribution of HRP reaction product in the nerve tissue was studied with light and electron microscopy. In 5-minute specimens, HRP was found in epidural and intradural vessel walls. At the nerve root level, HRP was detected in meningeal membranes but was not seen in periaxonal space. In addition to engaging the outer cell layers of the dorsal root ganglion (DRG) capsule, HRP was detected as a gradient among the peripherally located nerve cell bodies and sometimes among the emerging afferent axons. The 30-minute group demonstrated similar findings. The results confirm that HRP can reach the periaxonal spaces of lumbar DRG within 5 minutes after epidural application. Although the transport mechanism is not fully understood, the DRG may constitute an anatomical location allowing epidurally applied macromolecules entrance to the endoneurial space, either by direct diffusion or via vascular transport. The demonstrated transport route may have implications in the pathophysiology of sciatica in conjunction with lumbar disc herniation.

Autologous nucleus pulposus is known to have injurious effects on spinal nerve roots when applied epidurally. Both inflammatory and immunological mechanisms have been implicated in this regard. Various proinflammatory substances might be released or activated by nucleus pulposus and might affect the endoneural nerve root vessels. The present study assessed nucleus pulposus-induced early vascular reactions and the possibility of blocking these reactions with intravenous, high-dose, methylprednisolone pretreatment. In 25 pigs, the S2 and S3 nerve roots were exposed. In five pigs (control group), retroperitoneal fat was applied epidurally on the nerve roots, and the other 20 pigs had nucleus pulposus applied. This group was sub-divided into the treatment group (n = 8), in which the pigs were pretreated with intravenous high-dose methylprednisolone (30 mg/kg body weight), and the nontreatment group (n = 12), in which the pigs received a corresponding volume of saline solution. After 2 hours, Evans blue labeled albumin was injected intravenously 5 minutes before death. Endoneural extravasation of Evans blue labeled albumin was evaluated with fluorescence microscopy. A marked albumin leakage was found in 67% of the nontreated animals, in 25% of those in the treatment group, and in none of the control animals. These results demonstrate that nucleus pulposus can induce a rapid increase in endoneural vascular permeability in spinal nerve roots after epidural application. This increase can be partially prevented by pretreatment with high-dose methylprednisolone.

Nerve root dysfunction and sciatic pain in disc herniation are considered to be caused by mechanical compression and related to the presence of nucleus pulposus in the epidural space. Autologous nucleus pulposus has been shown to induce endoneural edema and to decrease nerve-conduction velocity in spinal nerve roots in experimental disc herniation models, and inflammatory mediators have been suggested to be involved in these mechanisms. Nitric oxide, a potent inflammatory mediator, is implicated in vasoregulation, neurotransmission, and neuropathic pain. Nitric oxide synthesis can be induced by different cytokines, e.g., tumor necrosis factor-alpha, which recently was shown to be of pathophysiological importance in experimental disc herniation. The enzyme nitric oxide synthase mediates the production of nitric oxide. Three series of experiments were performed in rat and pig disc herniation models to (a) investigate nitric oxide synthase activity in spinal nerve roots after exposure to autologous nucleus pulposus and (b) evaluate the effects of systemic treatment with aminoguanidine, a nitric oxide synthase inhibitor, on vascular permeability and nerve-conduction velocity. In a disc herniation model in the rat, calcium-independent nitric oxide synthase activity was measured in nerve roots exposed to nucleus pulposus; however, no nitric oxide synthase activity was detected in nerve roots from animals that underwent a sham operation, reflecting increased inducible nitric oxide synthase activity. In nucleus pulposus-exposed spinal nerve roots in the pig, the edema was less severe after systemic aminoguanidine administration than without aminoguanidine treatment. Aminoguanidine treatment also significantly reduced the negative effect of nucleus pulposus on nerve-conduction velocity in spinal nerve roots in the pig. These results demonstrate that nucleus pulposus increases inducible nitric oxide synthase activity in spinal nerve roots and that nitric oxide synthase inhibition reduces nucleus pulposus-induced edema and prevents reduction of nerve-conduction velocity. Furthermore, the results suggest that nitric oxide is involved in the pathophysiological effects of nucleus pulposus in disc herniation.

Compression of the spinal nerve roots may occur clinically at multiple levels at the same time; however, the basic pathophysiology of multi-level compression is largely unknown. In this study, the intraneural blood flow was analyzed continuously in the uncompressed segment between two compression balloons, with a pig used as an experimental model and a thermal diffusion method. At 10 mm Hg compression, there was a 64% reduction of total blood flow in the uncompressed segment compared with pre-compression values. Total ischemia occurred at pressures 10-20 mm Hg below the mean arterial blood pressure. After two-level compression at 200 mm Hg for 10 min, there was a gradual recovery of the intraneural blood flow towards the baseline. Recovery was less rapid and less complete after 2 h of compression. Double-level compression of the cauda equina can thus induce impairment of blood flow, not only at the compression sites, but also in the intermediate nerve segments located between two compression sites, even at very low pressures. These findings may have clinical importance in the understanding of the pathophysiology of multiple-level cauda equina compression.