Intrathecal Injection of Morphine Induces Pruritus via the NMDAR-Akt Signaling Pathway

Neuraxial opioids are routinely administered for pain management, but patients unavoidably suffer from irritating itch. The NMDAR-Akt signaling pathway is strongly implicated in morphine-induced tolerance and pain pathogenesis. Given that pain and itch share some common neurocircuits, this study aimed to evaluate the therapeutic potential of targeting this pathway in morphine-induced pruritus. Acute pruritus was induced in mice through intrathecal morphine injection. We assessed morphine-induced scratching behavior, analgesic effects, and spinal phosphorylation of NR2B and Akt. The roles of NMDAR antagonist, NR2B antagonist, Akt antagonist and agonist were investigated to elucidate the mechanisms underlying morphine-induced itch. Results showed coadministration of NMDAR or NR2B antagonists with morphine dose-dependently reduced morphine-induced scratching behavior. Inhibition of Akt totally abolished pruritus, whereas activation of Akt potentiated scratching responses. These interventions did not significantly affect morphine's antinociception. Furthermore, morphine-induced spinal Akt phosphorylation was reduced by NMDAR, NR2B, and Akt antagonists while enhanced by Akt agonist, with phosphorylation levels correlated with scratching behavior. The study concludes that intrathecal morphine induces pruritus through spinal upregulation of the NMDAR-Akt pathway in mice, highlighting potential therapeutic targets for relieving morphine-induced pruritus in clinical settings.