Functional interplay between gelatinases and hyperalgesia in endotoxin-induced localized inflammatory pain

The role of ECM-degrading proteinases in normal developmental processes and in pathological conditions is extensively studied. However, few reports de scribe the role ECM-degrading proteinases play in modulating hyperalgesia. The goal of this study is to describe the regulation of gelatinases during endotoxin mediated local inflammation, induced by intra plantar endotoxin ( ET; 1.25 mu g/50 mu l) injection in Balb/c mice, and to correlate that with hyperalgesia. ET injections induced hyperalgesia, as determined by hot pla te and paw pressure tests, which peaked by 24 h and recovered by 48 h post- injection. Contralateral paw of ET injected mice and saline injected paws i n control mice elicited no hyperalgesia. Zymography showed that ET and sali ne injected paws elicited increased gelatinase activity by 9 h after inject ion. However, only the former maintained high levels of expression of a 90 kD gelatinase up to at least 96 h post ET injection, while in the latter ge latinase expression was down regulated by 24 h. Interestingly, the 90-kD ge latinase was upregulated in the contralateral paw of the ET-injected mice b eyond 48 h post injection. Saline injection in that paw, during a time when gelatinases are upregulated, induced hyperalgesia. Intraperitoneal injecti on of either ZnCl2 (100 mu M), thymulin (5 mu g/100 mu l), pr morphine (2 m g/kg/100 mu l) reversed the ET-induced hyperalgesia and suppressed gelatina se activity. Furthermore, intraperitoneal injection of MPI, an ECM-degradin g proteinase inhibitor, reversed ET induced hyperalgesia. Taken together, t he above suggests that a functional interplay exists between gelatinase upr egulation triggered by ET injections and hyperalgesia. The exact mechanism underlying such correlation remains to be determined. (C) 2000 Internationa l Association for the Study of Pain. Published by Elsevier Science B.V.