Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1β-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord

We have reported recently that intrathecal (i.t.) injection of interleukin-1 beta (IL-1 beta), at a dose of 100 ng, induces induciblenitric oxide synthase (NOS) 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-1 beta-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 NOS 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-1 beta leads to a time-dependent up-regulation of phosphorylated p38 (p-p38) MAPK protein expression in the spinal cord 30240 min following IL-1 beta 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-1 beta injection. Intrathecal administration of either selective p38 MAPK, or JNK, or ERK inhibitor alone did not affect the thermal nociceptive threshold or NOS protein expression in the spinal cord. However, pretreatment with a p38 MAPK inhibitor significantly reduced the IL-1 beta-induced p-p38 MAPK expression by 38-49%, and nearly completely blocked the subsequent NOS expression (reduction by 86.6%), NO production, and thermal hyperalgesia. In contrast, both ERK and JNK inhibitor pretreatments only partially (approximate to 50%) inhibited the IL-1 beta-induced NOS expression in the spinal cord. Our results suggest that p38 MAPK plays a pivotal role in i.t. IL-1 beta-induced spinal sensitization and nociceptive signal transduction.