Threshold effect of G9a/Glp on peripheral nerve injury-induced hypersensitivity

BACKGROUND: Previous studies disclosed the pivotal role of methyltransferase complex G9a/Glp in the pathogenesis of neuropathic hypersensitivity induced by peripheral nerve injury. We observed that higher dose of G9a inhibitor improved nociceptive behavior, but the lower dose worsened pain. The aim of this study is to extensively observe the differential effect of various dosages of G9a/Glp inhibitors on nerve injury-induced allodynia. MATERIALS AND METHODS: After approval by the institutional ethical committee on pain research in conscious animals, C57BL/6 mice were used for measuring nociceptive behavior evoked with von Frey filaments after spared nerve injury. G9a/Glp inhibitor BIX01294 or UNC0638 was injected through the pre-buried intrathecal catheter. The dose–response curves of behavioral changes were depicted when inhibitors were administered once in bolus at the 14th day post spared nerve injury. Withdrawal behaviors were compared during the 49 days’ observation window after spared nerve injury with various dosages of inhibitors injected intrathecally for 14 days. RESULTS: Dose–behavior curves of a single bolus of both BIX01294 and UNC0638 displayed a “V”-shaped responses of allodynia withdrawal from lower through higher dose when measured at the 14th day post spared nerve injury. A threshold dose of 10.0 µg for BIX01294 and 80.0 µg for UNC0638 significantly worsened allodynia. However, daily bolus intrathecal injection for 14 days of both inhibitors lower or higher than these threshold doses prominently improved nociceptive behavior, producing contrasting results. On the same animal, threshold dose followed by a lower or higher dose with a 14 days’ interval also showed contrast effect on nociceptive behavior, and a lower or higher dose to threshold dose sequence of inhibitor administration was vice versa. CONCLUSIONS: Methyltransferase complex G9a/Glp has a threshold role in mediating peripheral nerve injury-induced hypersensitivity at its low level versus high level through inhibiting and facilitating the nociceptive behavior, respectively.