Δ-opioid receptor inhibition prevents remifentanil-induced post-operative hyperalgesia via regulating GluR1 trafficking and AMPA receptor function.

The interaction of remifentanil with glutamate systems has an important role in remifentanil-induced thermal and mechanical hyperalgesia. A previous study by our group suggested that the trafficking and function of glutamate receptor 1 (GluR1) subunits contributes to remifentanil-induced hyperalgesia by regulating the phosphorylation of GluR1 in dorsal horn neurons. The present study demonstrated that δ opioid receptor (DOR) inhibition prevented thermal and mechanical hyperalgesia, which was induced by remifentanil infusion via attenuating GluR1 subunit trafficking and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function in dorsal horn neurons. Sprague Dawley rats received a plantar incision and remifentanil infusion to induce a model of postoperative hyperalgesia. Thermal and mechanical pain was tested at 8 different time-points. Expression of AMPAR subunits GluR1 and DOR, as well as the phosphorylation status of GluR1 were evaluated by western blot analysis. Furthermore, the function of AMPAR in the spinal dorsal horn was measured by whole-cell patch-clamp recording. Remifentanil-induced thermal and mechanical hyperalgesia appeared after the 60-min infusions, reaching a peak level on day 2 and persisting for 5 days. Remifentanil infusion led to upregulation of membrane expression of the AMPAR subunit GluR1 and DOR (P=0.003 and 0.001, respectively) no change in total GluR1 and DOR expression levels (P=0.244 and 0.531, respectively). Selective DOR inhibitor naltrindole caused a reduction of remifentanil-induced hyperalgesia, which was accompanied by downregulation of membrane levels of GluR1 in the spinal cord (P=0.0013). In addition, DOR inhibition led to downregulation of GluR1 phosphorylated at Ser845. Furthermore, the AMPAR-mediated miniature excitatory post-synaptic current was increased in frequency and in amplitude in dorsal horn neurons (P=0.002 and 0.0011, respectively), which was decreased by incubation with naltrindole. Combined behavioral, western blot and electrophysiological evidence indicated that remifentanil-induced hyperalgesia was mediated by DOR activation, followed by phosphorylation-dependent GluR1 trafficking and AMPAR function enhancement in the spinal cord. DOR appears to be required for remifentanil and incision-induced hyperalgesia development and to be a potential biochemical target for treating opioid-induced postoperative hyperalgesia.