Nalbuphine attenuates morphine‐induced scratching by inhibiting PKCβ‐dependent microglial activation and p38 phosphorylation in male mice

• Published in: Journal of neuroscience research 2023-08, Vol.101 (8), p.1289-1304
• Main Authors: Tang, Yang, Li, Nan‐Qi, Ye, Liu‐Qing, Yang, Fan, Huang, Si‐Ting, Peng, Zhe, Xie, Jing‐Dun, Wan, Li
• Format: Article
• Language: English
• Subjects: Analgesia; Animals; Dorsal horn; Kinases; KOR; Male; Males; MAP kinase; Mice; Mice, Inbred C57BL; microglia; Microglia - metabolism; MIS; Morphine; Morphine - pharmacology; nalbuphine; Nalbuphine - metabolism; Nalbuphine - pharmacology; Opioid receptors (type kappa); p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; PKC; Protein kinase C; Protein Kinase C beta - metabolism; Protein Kinase C beta - pharmacology; Proteins; RRID:AB_2168681; RRID:AB_2298772; RRID:AB_2631098; RRID:AB_2650514; RRID:AB_2820253; RRID:AB_2868439; RRID:AB_628145; RRID:AB_670359; RRID:AB_779042; RRID:AB_839504; RRID:AB_881838; Scratching; Scratching behavior; Spinal cord
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.25189

Morphine‐induced scratching (MIS) is a common adverse effect associated with the use of morphine as analgesia after surgery. However, the treatment of MIS is less than satisfactory due to its unclear mechanism, which needs to be enunciated. We found that intrathecal (i.t.) injections of morphine significantly enhanced scratching behavior in C57BL/6J male mice as well as increased the expressions of protein kinase C β (PKCβ), phosphorylated p38 mitogen‐activated protein kinases (MAPK), and ionized calcium‐binding adapter molecule 1 (Iba1) within spinal cord dorsal horn. Conversely, using the kappa opioid receptor antagonist nalbuphine significantly attenuated scratching behavior, reduced PKCβ expression and p38 phosphorylation, and decreased spinal dorsal horn microglial activation, while PKCδ and KOR expression elevated. Spinal PKCβ silencing mitigated MIS and microglial activation. Still, knockdown of PKCδ reversed the inhibitory effect of nalbuphine on MIS and microglial activation, indicating that PKCδ is indispensable for the antipruritic effects of nalbuphine. In contrast, PKCβ is crucial for inducing microglial activation in MIS in male mice. Our findings show a distinct itch cascade of morphine, PKCβ/p38MAPK, and microglial activation, but an anti‐MIS pathway of nalbuphine, PKCδ/KOR, and neuron activation. PKCβ was activated, evoking microglia activation and p38 MAPK phosphorylation, resulting in morphine‐induced scratching. Whereas nalbuphine interrupts PKCβ activation and inhibits microglia/p‐p38 MAPK pathway, is via activate KOR‐PKCδ pathway. PKCβ and PKCδ compensate each other in MIS when one is absent.