The active metabolite of leflunomide, an immunosuppressive agent, reduces mechanical sensitivity in a rat mononeuropathy model.

Recent work has supported a key role for spinal cytokines and glial activation in the development and maintenance of persistent neuropathic pain after peripheral nerve injury. This study was undertaken to determine whether the active metabolite of leflunomide (A77 1726), an anti-inflammatory and immunosuppressive agent, could attenuate persistent mechanical allodynia in a rodent L5 spinal nerve transection model. A77 1726 was administered daily intraperitoneally (0.01 to 10 mg/kg) beginning 1 day before nerve transection. In a separate experiment, A77 1726 was administered daily intrathecally (0.001 to 10 microg in 40 microL) beginning 1 hour before nerve transection. Both systemic and centrally administered A77 1726 significantly reduced mechanical allodynia across the time course of the study (P < .05). A77 1726 attenuated glial activation on day 10 after transection at doses that reduced mechanical sensitivity. In addition, central A77 1726 administration decreased spinal expression of major histocompatibility complex class II. Spinal interleukin-6 levels were unaffected by A77 1726 treatment. This study provides further evidence implicating a contribution of spinal glial activation in the development and maintenance of persistent neuropathic pain. Furthermore, this study reports that systemic and central administration of the active metabolite of leflunomide, an immunosuppressive agent used for the treatment of rheumatoid arthritis, produces an antiallodynic action in a rodent mononeuropathy model.