Cathepsin S in the spinal microglia facilitates morphine-induced antinociceptive tolerance in rats.

Microglia-derived lysosomal cysteine protease cathepsin S (CatS) is increasingly recognized as important mediators to exaggerate nociceptive signaling. However, the patterns and functional roles of CatS in morphine tolerance have never been investigated. Here, we showed that mature form of CatS was exclusively upregulated in the spinal microglia following chronic morphine treatment. Pharmacological blockade of CatS before each morphine treatment prolonged the efficacy of morphine analgesia. Correspondingly, inhibition of CatS suppressed activation of spinal microglia and phosphorylated p38 MAPK. Finally, intrathecal injection of selective microglia inhibitor minocycline reduced upregulation of mature CatS induced by chronic morphine treatment. Our data provide novel insight into the cellular mechanisms underlying morphine antinociceptive tolerance and highlight CatS as a therapeutic target for preventing morphine tolerance.