RNA from rat dorsal root ganglia was analyzed in search of potentially beneficial cytokines that are induced in dorsal root ganglia by nerve injury. By reverse transcription, the PCR, and Southern blotting, interleukin-6 mRNA was detected during development but not in normal adult dorsal root ganglia, reappeared within 1 d of sciatic nerve transection, was maximally increased after 2 and 4 d, and decreased below the threshold of detection within 1 week. By RNase protection assay, interleukin-6 mRNA was consistently present in RNA from dorsal root ganglia removed from rats 4 d following transection but not in control dorsal root ganglia. Interleukin-6 bioactivity was also present in dorsal root ganglia following nerve injury. By in situ hybridization, interleukin-6 mRNA was localized within large and medium- sized axotomized neurons. In summary, some sensory neurons respond to axotomy with a brisk transient increase in synthesis of interleukin-6. Injury to the sciatic nerve also induced mRNAs for interleukin-1 beta and tumor necrosis factor-alpha in dorsal root ganglia. The inductions of interleukin-1 beta and tumor necrosis factor-alpha mRNAs were later and more sustained than that of interleukin-6 mRNA. The cellular sources of these two cytokines have not been defined.

Partial nerve injury is a potential cause of distressing chronic pain for which conventional analgesic treatment with opiates or anti-inflammatory agents is not very effective. Constriction nerve injury, widely used to study neuropathic pain, was shown here to induce interleukin-6 (IL-6) mRNA in a subset of rat primary sensory neurons. When we inflicted chronic nerve constriction on mice with null mutation of the IL-6 gene, the hypersensitivity to cutaneous heat and pressure that is induced in wild-type mice was not evident, the loss of substance P in sensory neurons was excessive and the induction of galanin in central sensory projections was reduced. In additional experiments, intrathecal infusion of IL-6 in rats was shown to stimulate synthesis of galanin in approximately one-third of lumbar dorsal root ganglion neurons. The results of these experiments indicate that endogenous IL-6 mediates some of the hypersensitive responses that characterize peripheral neuropathic pain, and influences two neuropeptides that have been implicated in pain transmission.

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