Intraneural injection of interleukin-1β and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain

Proinflammatory cytokines are mediators of inflammatory and neuropathic pain. Here, we investigated pain-related behavior in rats after intraneural injection of different doses of rat recombinant interleukin-1β (rrIL-1β) and tumor necrosis factor-alpha (rrTNF) into the sciatic nerve. Doses ranged between 0.25 and 2500 pg/ml for rrIL-1β and 0.25-250 pg/ml for rrTNF. Thermal hyperalgesia as measured according to the Hargreaves method was most prominent with 2.5 pg/ml of rrIL-1β or rrTNF. Mechanical allodynia as assessed using von Frey hairs was seen consistently with 2.5 pg/ml of rrIL-1β and 0.25-2.5 pg/ml of rrTNF. Higher and lower doses had no significant effect on pain-related behavior. Morphometric analysis of semithin sections of the sciatic nerve 10 days after the injections revealed no significant fiber loss. The fiber size distribution was not significantly altered by any of the treatments. Particularly with injections of rrIL-1β, an increase of epineurial macrophages was observed at all doses. The immunohistochemical expression of cellular markers of neuronal damage (activating transcription factor 3) or activation (phosphorylated p38 mitogen-activated kinase, NF-kappa B p65) in dorsal root ganglia (DRG) tended to increase with both cytokine injections. However, this did not reflect the extent of behavioral changes. In summary, we found a bell-shaped dose-response curve for the algesic effects of rrIL-1β and rrTNF, peaking at doses equivalent to those of endogenous cytokines released locally after nerve injury. The absence of corresponding morphological changes in nerves supports the concept of a functional effect of the cytokines at these doses.