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.