Nalbuphine Attenuates Microglial Activation and Inhibits Morphine-Induced Scratching via Regulation of PKCδ and p38 Signaling in Mice

Abstract

Morphine-induced scratching (MIS) is a common issue in patients receiving clinical postoperative morphine intrathecal injections. The kappa opioid receptor (KOR) agonist nalbuphine is known to prevent and reduce MIS, but the underlying mechanism has remained unclear. Here, we found that protein kinase C (PKCβ) in the spinal cord dorsal horn was co-expressed with ionized calcium binding adapter molecule 1 (Iba1) and increased after morphine intrathecal (i.t.) injections in mice. Although knockdown PKCβ inhibited microglial activation and attenuated MIS, but nalbuphine can blocked MIS by promoting PKCδ expression rather than PKCβ expression, suggesting that antipruritic effect of nalbuphine is due to activation of the KOR/PKCδ pathway and that MIS is both PKCβ-dependent and closely related to microglial activation. Moreover, we also found that PKCδ could retroegulation microglial activation, thereby reversing nalbuphine’s inhibition of MIS and resulting in increased itching behaviors. Notably, microglial activation is required for p-p38 signaling in MIS. These data together suggest that nalbuphine activates KOR, so as to inducing the activation of PKCδ, which may in turn retroegulation microglial function and decrease phosphorylate p38, ultimately inhibiting MIS. Our research therefore indicates that a previously unknown KOR-PKCδ-microglia-p38 pathway in the spinal cord may underlie nalbuphine’s antipruritic effect.