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Tumour necrosis factor-alpha ( TNF-alpha) has been proposed as one of the key mediators of inflammatory diseases of the CNS such as multiple sclerosis. It has been shown to induce the expression of adhesion molecules which is a prerequisite for the transmigration of immune cells through the blood-brain barrier. We therefore investigated the role of TNF-alpha in the expression and release of vascular cell adhesion molecule-1 (VCAM-1) in cultures of human cerebral endothelial cells (HCEC) in comparison with peripheral blood mononuclear cells (PBMC). A time- and dose-dependent expression of VCAM-1 and release of soluble VCAM-1 was detected in HCEC but not PBMC. TNF-alpha-induced release of soluble VCAM-1 was further increased by cotreatment with interferon-beta (IFN-beta), while IFN-beta alone did not affect VCAM-1 expression or the release of soluble VCAM-1. In addition, we observed that preincubation of PBMC with soluble VCAM-1 completely blocked their adhesion to HCEC. In conclusion, the proinflammatory effect of TNF-alpha on HCEC, which involves the induction of VCAM-1 expression and cellular adhesion, is followed by the consecutive effects of soluble VCAM-1 release in blocking adhesion and downregulating further cellular infiltration. Increasing soluble VCAM-1 release during active inflammation could be another mechanism by which IFN-beta treatment exerts protective effects in multiple sclerosis patients.

One of the most commonly used experimental animal models for neuropathic pain is the chronic constriction injury (CCI) where four loose ligatures are tied around the sciatic nerve. One disadvantage of this model is the introduction of foreign material into the wound, which causes a local inflammatory reaction. Thus the distinction between the neuropathic and the inflammatory component of pain is difficult in this model. In order to produce a pure nerve lesion, we performed a partial sciatic nerve transection (PST; a modification of the Seltzer model) in female Sprague-Dawley rats and compared behavior and nerve pathology. These rats developed thermal hyperalgesia and mechanical allodynia comparable to the CCI model. Recovery of these symptoms was found between days 40 and 60 after the nerve lesion. Some animals still showed symptoms on day 101, which was associated with a neuroma formation. The main pathological findings in the endoneurium in nerve segments distal to the lesion were edema, loss of myelinated fibers and increase in endoneurial cells, especially macrophages. In the epineurium the number of macrophages was strikingly increased after CCI compared with PST, indicating that the response of the immune system is different in a structural lesion with and without foreign material. In conclusion, PST is a pure nerve injury model without an epineurial inflammatory component due to foreign material and is therefore well suited for studying the role of local endoneurial processes in the development and maintenance of neuropathic pain. Also, the importance of regeneration in the termination of hyperalgesia can convincingly be shown in this model.

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