Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord.
We have reported recently that intrathecal (i.t.) injection of interleukin-1beta (IL-1beta), at a dose of 100 ng, induces inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in the spinal cord and results in thermal hyperalgesia in rats. This study further examines the role of mitogen-activated protein kinase (MAPK) in i.t. IL-1beta-mediated iNOS-NO cascade in spinal nociceptive signal transduction. All rats were implanted with an i.t. catheter either with or without an additional microdialysis probe. Paw withdrawal latency to radiant heat is used to assess thermal hyperalgesia. The iNOS and MAPK protein expression in the spinal cord dorsal horn were examined by western blot. The [NO] in CSF dialysates were also measured. Intrathecal IL-1beta leads to a time-dependent up-regulation of phosphorylated p38 (p-p38) MAPK protein expression in the spinal cord 30-240 min following IL-1beta injection (i.t.). However, neither the phosphorylated extracellular signal-regulated kinase (p-ERK) nor phosphorylated c-Jun NH2-terminal kinase (p-JNK) was affected. The total amount of p38, ERK, and JNK MAPK proteins were not affected following IL-1beta injection. Intrathecal administration of either selective p38 MAPK, or JNK, or ERK inhibitor alone did not affect the thermal nociceptive threshold or iNOS protein expression in the spinal cord. However, pretreatment with a p38 MAPK inhibitor significantly reduced the IL-1beta-induced p-p38 MAPK expression by 38-49%, and nearly completely blocked the subsequent iNOS expression (reduction by 86.6%), NO production, and thermal hyperalgesia. In contrast, both ERK and JNK inhibitor pretreatments only partially (approximately 50%) inhibited the IL-1beta-induced iNOS expression in the spinal cord. Our results suggest that p38 MAPK plays a pivotal role in i.t. IL-1beta-induced spinal sensitization and nociceptive signal transduction.
Sung
Chun-Sung
CS
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Wen
Zhi-Hong
ZH
Chang
Wen-Kuei
WK
Chan
Kwok-Hon
KH
Ho
Shung-Tai
ST
Tsai
Shen-Kou
SK
Chang
Yi-Chen
YC
Wong
Chih-Shung
CS
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003956:Dialysis / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D008297:Male; D009569:Nitric Oxide / Q000134:cerebrospinal fluid; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases