The effect of thalidomide on behavioral signs of hyperalgesia and allodynia following chronic constriction injury to sciatic nerve in a rat

Painful peripheral neuropathies involve both axonal damage and an inflammatory response of the nerve. The role of later was investigated by administration of the immunomodulatory drug thalidomide to an experimental model of painful peripheral neuropathy. Immune cell infiltration, and increased endoneurial levels of pro-inflammatory cytokines (including tumor necrosis factor α, interleukin-1 β, and interleukin-6) have been detected at the site of experimental nerve injury. Tumor necrosis factor alpha (TNF), a protein secreted by activated macrophage, participates in inflammatory responses and may be involved in the mechanisms of neuropathic pain. TNF enhances the release of arachidonnic acid and the synthesis of eicosanoids, especially prostaglandin E₂ by the induction of phospholipase A₂ and cyclo- oxygenase activating respectively. We have examined the effect of thalidomide, a selective blocker of TNF-production in active macrophages, on the behavioral signs of hyperalgesia and allodynia following chronic constriction injury to sciatic nerve in a rat. Twenty-eight adult male rats (250-350 g) were anesthetized with sodium pentobarbital (45 mg/kg, i.p.). The sciatic nerve was exposed at mid-thigh by blunt dissection through the biceps femoris. Four ligatures (chromic gut 4-0) were tied loosely around this nerve at about 1 mm spacing. The sciatic nerve were not ligated on the opposite side. Rats were tested on the paw to estimate heat-hyperalgesia, mechano- hyperalgesia, cold-allodynia, mechano-allodynia and sedative effect. The subjects were separated into four groups: the first was given orally thalidomide (50 mg/kg) in 200 μg of vegetable oil from the surgery day to end of the experiment (thalidomide group), the second was given thalidomide from the surgery day to day 5 post-surgery (preemptive group), the third was given thalidomide from day 6 post-surgery to end of the experiment (post group) and the fourth was given vegetable oil only (vehicle group). Thalidomide or vehicle were given two hours before surgery and then daily thereafter for fifteen days. Statistically, abnormal pain response on the treatment side was inhibited in the thalidomide and preemptive groups. The sedative effect of thalidomide showed no change in latencier and von Frey hair ranks. The results indicate that administration of thalidomide, this blocking production of TNF, reduces pain-related behavior. We concluded that an inflammatory response (pro-inflammatory cytokines) of the sciatic nerve produces neuropathic pain sensations in a distant region.