Patients with double or multiple levels of spinal steno­sis seem to have more pronounced symptoms than patients with stenosis only at one level (29). The pre­sented model was modified to address this interesting clinical issue. Using two balloons at two adjacent disc levels, which resulted in a 10-mm uncompressed nerve segment between the balloons, induced a much more pro­nounced impairment of nerve impulse conduction than had been previously found at corresponding pressure lev­els (30). For instance, a pressure of 10 mm Hg in two bal­loons induced a 60% reduction of nerve impulse ampli­tude during 2 hours of compression, whereas 50 mm Hg in one balloon showed no reduction.

There are some experimental observations that indi­cate that mechanical nerve deformation per se may induce impulses that could be interpreted as pain by the central nervous system. Howe and collaborators found that mechanical stimulation of nerve roots or peripheral nerves resulted in nerve impulses of short duration, and that these impulses were prolonged if the nerve tissue had been exposed to mechanical irritation by a chromic gut ligature for 2 to 4 weeks (52). The same results were obtained in an in vitro system using rabbit ner ve roots (53). However, in this setup it was also evident that the dorsal root ganglion was more susceptible to mechani­cal stimulation than the nerve roots. The dorsal root ganglion has drawn a special interest in this regard, and an increase in the level of neurotransmitters related to pain transmission has been found in the dorsal root gan­glion in response to whole body vibration of rabbits (54). A similar increase also has been seen in the dorsal root ganglion and nerve root after local constriction of the same nerve root (40). In vivo models of pain behav­ior have demonstrated that a severe mechanical defor­mation, such as ligation, of the nerve root generally is not painful (55–57). However, it seems that if chromic gut sutures are used, the additional irritation makes the mechanical compression painful. Recent studies have shown that disc incision with leakage of nucleus pulpo­sus into the epidural space or a light mechanical defor­mation and slight medial displacement of the nerve root, does not produce pain behavior in a rat model, whereas the combination of the two factors produces pain (58–60). This is discussed in the following.

Interesting observations have been made regarding contact pressure between the nerve root and the disc in patients with lumbar disc herniation (61). Nerve root pressure before discectomy varied from 7 to 256 mm Hg (mean, 53 mm Hg). The magnitude of nerve root pressure

Although the combination of a mechanical component and the presence of nucleus pulposus seems to be a pre­requisite to produce changes in the in vivo situation, neu­rophysiologic studies have demonstrated that the mere application of nucleus pulposus may induce increased neuronal pain transmission (89). This may indicate that pain behavior assessment is a gross instrument to detect pain and that nucleus pulposus may induce pain in the absence of a mechanical component as well.

It is difficult to relate the observed histologic changes of nerve tissue as induced by nucleus pulposus to direct neu­rotoxic effects or ischemia. There is always reason to assume that there are neurotoxic substances acting on the axons present in the nucleus pulposus. How e v er, histologic observations indicate that the changes are focal and mainly found in the center of the nerve roots, resembling a mononeuritis simplex induced by nerve infarction caused by embolism of the intraneural vessels (6,71,98). Particu­larly in view of the work of Jayson et al. that indicate an impairment of the venous outflow from the nerve roots owing to periradicular v ascular changes, one must consider vascular impairment as a highly interesting factor (99–102). Even relatively large molecules deposited in the epidural space may be found in the intraneural vessels of the adjacent nerve roots within seconds after application (103). Considering the possibility of epidurally placed sub­stances to penetrate the relatively impermeable dura, cross over the CSF, and then diffuse through the root sheath and into the axons, this vascular route may seem more rele v ant. As mentioned, nucleus pulposus seems to have certain inflammatory properties (6,78–80,104). Because many inflammatory mediators are involved in vascular and rheo­logic phenomena such as coagulation, one may suspect that vascular impairment of the nerve root may result from vascular embolism. In fact, it was observed in a vital microscopic study that the presence of nucleus pulposus may induce thrombus formation in microvessels (78). Inflammatory mediators might also exert a direct effect on the myelin sheaths, as indicated by an electron microscopic study of nerve roots exposed to autologous nucleus pulpo­sus in the pig (71). There were significant injuries of Schwann cells with vacuolization and disintegration of the Schmidt-Lanterman incisures, which closely resembles the

Cytokines as Mediators of Nerve Dysfunction and Pain

Tumor necrosis factor is known to be a regulatory proin­flammatory cytokine that has both specific biologic ef fects as well as the ability to up-regulate and act synergistically with other cytokines, such as IL-1B and IL-6 (126–131). Immediately after nerve injury, TNF is released and up­regulated by Schwann cells at the site of nerve injury (132). This is followed by the release and up-regulation of TNF in many other endoneurial cells, including endothe­lial cells, fibroblasts, and mast cells. Tumor necrosis factor also is produced by chondrocytes and disc cells (125, 133–136). The local production of TNF is the stimulus that results in macrophage attraction to the injury site (66), which then contributes massively to the concentration of proinflammatory cytokines in the injured tissue. Several studies have clearly shown that blocking TNF production or delaying the invasion of macrophages to the site of nerve injury results in reduced or delayed neuropathologic change and reduced hyperalgesia (81,137). When perform­ing a meta-analysis on the biologic or pathophysiologic effects induced by TNF and nucleus pulposus, one may find that there is almost a perfect match. For instance, TNF is known to induce axonal and m y elin injury similar to that observed after nucleus pulposus application (138–144), intravascular coagulation (145–147), and increased vascu­lar permeability (147). Tumor necrosis factor is also known to be neurotoxic (141,143,148,149) and to induce painful behavioral changes (138,150) as well as ectopic nerve activity when applied locall y (139,151). Interestingly, TNF is sequestered in a membrane-bound form and is activated after shedding by certain enzymes. Matrix metallopro­teinases (MMP) are particularly important in this regard. MMP-9 and MMP-2 are up-regulated immediately after a