Chemokine CCL7 regulates spinal phosphorylation of GluA1-containing AMPA receptor via interleukin-18 in remifentanil-induced hyperalgesia in rats

Abstract

BackgroundRemifentanil-induced hyperalgesia (RIH) may be a potential component for acute confusional state and chronic pain after surgery, but specific mechanism remains elusive. Chemokines and inflammatory mediators associated neuroinflammation is involved in central nociceptive sensitization. The contribution of AMPA receptor to excitatory synaptic transmission in pathologic pain has been indicated. This study investigated whether chemokine CCL7 modulated spinal phosphorylation of AMPA receptor via interleukin (IL)-18 in a rat model of RIH. MethodsMechanical allodynia and thermal hyperalgesia after remifentanil infusion were verified by assessment of paw withdrawal threshold and paw withdrawal latency, respectively. A neutralizing antibody against CCL7, IL-18 antagonist and recombinant CCL7 were employed to identify the mechanisms. Levels of CCL7 and its receptors, expressions of IL-18 and its receptor IL-18R, and the phosphorylation of GluA1 in the spinal cord dorsal horn were evaluated. ResultsWe reported that acute exposure to remifentanil caused and maintained behavioral RIH with up-regulation of expression in CCL7/CCR2 and IL-18/IL-18R and the phosphorylation of GluA1 in the dorsal horn. Spinal inhibition of CCL7/CCR2 impaired RIH, spinal expression of IL-18/IL-18R and the phosphorylation of GluA1. Central blockage of IL-18/IL-18R reduced spinal phosphorylation of GluA1 and behavioral RIH. Also, intrathecal injection of exogenous CCL7 facilitated acute pain behaviors and spinal phosphorylation of GluA1 in naïve mice, which was suppressed by co-administration of IL-18 antagonist. ConclusionOur current findings demonstrate that spinal CCL7/CCR2 modulation of GluA1-containing AMPA receptor activation via IL-18 and IL-18R over-expression is an important pathogenesis of remifentanil-induced hyperalgesia in rats.