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Thalidomide reduces thermal hyperalgesia and mechanical allodynia in chronic constrictive sciatic nerve injury (CCI). Since thalidomide mainly inhibits tumor necrosis factor alpha (TNF-α) synthesis with less well defined effects on other cytokines, we investigated the effect of the drug on the expression of the proinflammatory cytokines TNF-α, interleukin-1β (IL-1β) and interleukin 6 (IL-6), and of the anti-inflammatory cytokine interleukin-10 (IL-10) in the lesioned rat sciatic nerve. The increase of endoneurial TNF-α during the first week after CCI was reduced after thalidomide treatment, as shown with immunohistochemistry and enzyme-linked-immunosorbent assay. In contrast, endoneurial IL-1β-immunoreactivity (IR) and IL-6-IR were not altered by thalidomide treatment, nor was macrophage influx. Recruitment of epineurial IL-10 immunoreactive macrophages as well as the recovery of injury-induced depletion of endoneurial IL-10-IR was enhanced by thalidomide treatment. To control for central plasticity as another factor for the effects of thalidomide, the spinal cord was analyzed for changes in neurotransmitters. The decrease in CGRP-IR and SP-IR in the dorsal horn of operated animals was not influenced by treatment. In contrast, the increase in met-enkephalin observed in the dorsal horn of operated animals was further enhanced in the thalidomide-treated animals. The study elucidates some of the complex alterations in CCI and its modulation by thalidomide, and provides further evidence for a possible therapeutic benefit of cytokine-modulating substances in the treatment of neuropathic pain.