Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain

The expression of interleukin-1 beta and tumor necrosis factor has previous ly been shown to be up-regulated in the spinal cord of several rat mononeur opathy models. This present study was undertaken to determine whether block ing the action of central interleukin-1 beta and tumor necrosis factor atte nuates mechanical allodynia in a gender-specific manner in a rodent L5 spin al nerve transection model of neuropathic pain, and whether this inhibition occurs via down-regulation of the central cytokine cascade or blockade of glial activation. Interleukin-1 receptor antagonist or soluble tumor necros is factor receptor was administered intrathecally via lumbar puncture to ma le Holtzman rats in a preventative pain strategy, in which therapy was init iated 1 h prior to surgery. Administration of soluble tumor necrosis factor receptor attenuated mechanical allodynia, while interleukin-1 receptor ant agonist alone was unable to decrease allodynia. Interleukin-1 receptor anta gonist in combination with soluble tumor necrosis factor receptor, administ ered to both male and female rats in a preventative pain strategy, signific antly reduced mechanical allodynia in a dose-dependent manner (P < 0.01). T he magnitude of attenuation in allodynia was similar in both males and fema les. Immunohistochemistry on LS spinal cord revealed similar astrocytic and microglial activation regardless of treatment. At days 3 and 7 post-transe ction, animals receiving daily interleukin-1 receptor antagonist in combina tion with soluble tumor necrosis factor receptor exhibited significantly le ss interleukin-6, but not interleukin-1<beta>, in the L5 spinal cord compar ed to vehicle-treated animals. In an existing pain paradigm, in which treat ment was initiated on day 7 post-transection, interleukin-1 receptor antago nist in combination with soluble tumor necrosis factor receptor attenuated mechanical allodynia (P < 0.05) in male rats. These findings further support a role for central interleukin-1<beta> and t umor necrosis factor in the development and maintenance of neuropathic pain through induction of a proinflammatory cytokine cascade. (C) 2001 IBRO. Pu blished by Elsevier Science Ltd. All rights reserved.