Intraneural injection of interleukin-1beta 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-1beta (rrIL-1beta) and tumor necrosis factor-alpha (rrTNF) into the sciatic nerve. Doses ranged between 0.25 and 2500pg/ml for rrIL-1beta and 0.25-250pg/ml for rrTNF. Thermal hyperalgesia as measured according to the Hargreaves method was most prominent with 2.5pg/ml of rrIL-1beta or rrTNF. Mechanical allodynia as assessed using von Frey hairs was seen consistently with 2.5pg/ml of rrIL-1beta and 0.25-2.5pg/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-1beta, 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-1beta 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.
Zelenka
Marek
M
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, D-97080 Würzburg, Germany.
Schäfers
Maria
M
Sommer
Claudia
C
D051700:Activating Transcription Factor 3; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D048429:Cell Size / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D053331:Ectodysplasins; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007267:Injections / Q000379:methods; D007375:Interleukin-1 / Q000633:toxicity*; D008565:Membrane Proteins / Q000378:metabolism; D048292:Mitogen-Activated Protein Kinase 13 / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D010812:Physical Stimulation / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000139:chemically induced* / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D000097782:NF-kappaB-Inducing Kinase
D051700:Activating Transcription Factor 3; D053331:Ectodysplasins; D007375:Interleukin-1; D008565:Membrane Proteins; D048292:Mitogen-Activated Protein Kinase 13; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C497108:Atf3 protein, rat