Abstract
Treatment of remifentanil-induced postoperative hyperalgesia (RIH) remains a clinical challenge because the mechanisms are not fully understood. Matrix metalloproteinase-9 (MMP-9) is a key component in neuroinflammation because of its facilitation of pro-inflammatory cytokine maturation. Therefore, inhibition of MMP-9 may represent a novel therapeutic approach to the treatment of RIH. Sprague-Dawley rats were randomly divided into three groups: Control, Incision and Remifentanil. A right plantar surgical incision was performed in Group Incision, and intraoperative remifentanil (0.04 mg/kg, 0.4 ml) was infused subcutaneously for 30 min in Group Remifentanil. The results indicated that intraoperative remifentanil induced an up-regulation and activation of MMP-9 in DRGs but not spinal cords. MMP-9 was expressed primarily in DRG neurons co-expressing mu opioid receptors (MOR), and elicited interleukin-1β (IL-1β) cleavage in DRG neurons and satellite glial cells (SGCs). Intraperitoneal injection of N-acetyl-cysteine (NAC), a broadly used safe drug, significantly attenuated RIH via suppressing the activation of MMP-9 in DRGs. NAC inhibited the cleavage of IL-1β in DRGs, which is a critical substrate of MMP-9, and markedly suppressed glial activation and neuron excitability in spinal dorsal horn induced by remifentanil. These results demonstrated that NAC can effectively alleviate RIH via powerfully inhibiting MMP-9 activation in DRGs.
Highlights
Remifentanil is commonly administered intravenously during general anesthesia
The results revealed an increase in Matrix metalloproteinase (MMP)-9 activity in the dorsal root ganglia (DRG) at 24 h and 48 h after subcutaneous remifentanil infusion during surgery in group R as compared with group I (P < 0.0001)
We postulate that up-regulation and activation of neuronal Matrix metalloproteinase-9 (MMP-9), and subsequent IL-1β cleavage in DRGs following intraoperative remifentanil infusion triggers glial activation and sensory neuron excitability in spinal cord dorsal horn, promoting the development of remifentanil-induced postoperative hyperalgesia (RIH)
Summary
Remifentanil is commonly administered intravenously during general anesthesia. It has contrary pronociceptive actions and promotes postoperative hyperalgesia [1, 2]. The mechanisms of remifentanil-induced hyperalgesia (RIH) might be related to spinal N-methyl-d-aspartate receptor (NMDAR)-dependent central sensitization [3, 4]. Administration of selective chemokine (C-X-C motif) receptor 2 (CXCR2) antagonist SB225002, glycogen synthase kinase-3β (GSK-3β) inhibitor TDZD8, cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine, or alpha-7 nicotinic acetylcholine receptor (α7-nAchR) agonists PHA-543613 can attenuate RIH via regulating the expression and function of spinal NMDAR [5, 10,11,12]. A safe drug, which is effective on RIH and can be used in the clinic is not yet available
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