Neuropathic pain is characterized by spontaneous
pain,
hyperalgesia, and
allodynia. The aim of this study was to investigate whether
KMUP-1 (7-[2-[4-(2-
chlorobenzene)piperazinyl]ethyl]-
1,3-dimethylxanthine) could improve
pain hypersensitivity and reduce inflammatory mediators, and also explore possible mechanisms in the rat sciatic nerve using bilateral chronic constriction injury (CCI) to induce
neuropathic pain. Sprague-Dawley rats were randomly divided into four groups:
Sham, Sham+KMUP-1, CCI, and CCI+KMUP-1.
KMUP-1 (5 mg/kg/day) was injected intraperitoneally starting at day 1 after surgery. Mechanical and thermal responses were assessed before surgery and at days 3, 7, and 14 after CCI. Sciatic nerves around the injury site were isolated for Western blots and
enzyme-linked
immunosorbent assay to analyze
protein and
cytokine levels. The results show that
thermal hyperalgesia and
mechanical allodynia were reduced in the
KMUP-1 treated group as compared to that in the CCI group. Inflammatory
proteins (COX2, iNOS, and nNOS) and proinflammatory
cytokines (TNF-α and IL-1β) induced by CCI were decreased in the
KMUP-1 treated group at day 7 after surgery.
KMUP-1 also inhibited
neuropathic pain-related mechanisms, including p38 and ERK activation, but not JNK. Furthermore,
KMUP-1 blocked IκB phosphorylation (p-IκB) and phospho-nuclear factor κB (p-NF-κB) translocation to nuclei. Double immunofluorescent staining further demonstrated that p-IκB (an
indicator of activated NFκB) and p-NFκB
proteins were almost abolished by
KMUP-1 in peripheral macrophages and spinal microglia cells at day 7 after surgery. On the basis of these findings, we concluded that
KMUP-1 has antiinflammatory and antihyperalgesia properties in CCI-induced
neuropathic pain via decreases in MAPKs and NF-κB activation.