[Animal studies on neuropathic pain: the role of cytokines and cytokine receptors in pathogenesis and therapy].

When pain becomes chronic this is a process that takes place at several levels of the peripheral and central nervous systems. In recent years, proinflammatory substances like bradykinin, prostaglandins and signal molecules like cytokines have been identified as allogenic factors. In the present paper we examined whether cytokines play a role also in non-inflammatory peripheral nerve lesions, i.e. whether they are of importance in the causation of pain in general and whether their antagonists can be used therapeutically. The development of pain after peripheral nerve lesion in animal models follows the process of Wallerian degeneration. During Wallerian degeneration the expression of proinflammatory cytokines in the nerve is upregulated. Here we studied the temporal course of cytokine expression with several different analytical methods, analyzing tumor necrosis factor-alpha (TNF) and interleukin-beta (IL-beta) in the mouse model of chronic constrictive injury (CCI) of the sciatic nerve. This model is associated with reproducible pain related behavior in the animals. We found an early increase of TNF 12 hours after injury. Neutralizing antibodies to TNF were able to reduce the hyperalgesia that evolved due to the nerve injury. As TNF exerts its effects via two receptors, TNF receptor 1 (TNF-R1) and TNF receptor 2 (TNF R2), we also investigated, which of the receptors is relevant to the causation of pain in this model. It turned out that antibodies to TNF-R1, but not to TNF-R2 reduced hyperalgesia, indicating that TNF-R1 is the receptor concerned. Neutralizing antibodies to IL-1 receptor and to IL-6 receptor also reduced pain related behavior. These results lead to the conclusion that proinflammatory cytokines are involved not only in inflammatory pain but also in neuropathic pain. Therapeutic strategies involving cytokine inhibition have been tested experimentally and are already being used in preliminary clinical studies in immune-mediated diseases. In the future, they might be a useful addition to the range of treatments for patients with neuropathic pain.