Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord.
The effect of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) on the inducible nitric oxide synthase-nitric oxide (iNOS-NO) cascade in nociceptive signal transduction was examined in the intact rat spinal cord. All rats were implanted with an intrathecal (i.t.) catheter; some were also implanted with an i.t. microdialysis probe. The paw withdrawal latency to radiant heat was used to assess thermal hyperalgesia. The iNOS protein expression in the spinal cord dorsal horn was examined by western blot analysis and NOS activity assay. NO production in the CSF dialysate was also measured. IL-1beta i.t. (100 ng) produced thermal hyperalgesia from 4 to 24 h after i.t. injection. The iNOS protein expression was induced at 4 h after i.t. IL-1beta injection, peaked at the 6th hour, and disappeared at 24 h. The iNOS activity showed a similar time-dependent change as the iNOS protein expression. NO release increased by 1.1- to 1.9-fold between 4 and 12 h, also with a peak at the 6th hour, after i.t. IL-1beta administration. Pretreatment with the iNOS inhibitor 1400W (10 microg, i.t.) 1 h before i.t. IL-1beta injection prevented all the responses of IL-1beta. Neither 1400W nor artificial CSF (aCSF) affected the thermal nociceptive threshold and NO production. These results demonstrate that i.t. administration of IL-1beta induced thermal hyperalgesia by activating the iNOS-NO cascade in the rat spinal cord. On the basis of the present findings, we suggest that i.t. administration of iNOS inhibitors may have potential in the treatment of inflammatory and neuropathic pain syndromes.
Sung
Chun-Sung
CS
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Wen
Zhi-Hong
ZH
Chang
Wen-Kuei
WK
Ho
Shung-Tai
ST
Tsai
Shen-Kou
SK
Chang
Yi-Chen
YC
Wong
Chih-Shung
CS
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000201:enzymology* / Q000503:physiopathology; D007278:Injections, Spinal; D007375:Interleukin-1 / Q000008:administration & dosage / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000134:cerebrospinal fluid; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology*; D010465:Perception / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013268:Stimulation, Chemical; D013997:Time Factors
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat