N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia
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Yue Liu1,*, Yuan Ni1,*, Wei Zhang1, Yu-E Sun1, Zhengliang Ma1, Xiaoping Gu1
1Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China
*These authors contributed equally to this work
Zhengliang Ma, email: firstname.lastname@example.org
Xiaoping Gu, email: email@example.com
Keywords: remifentanil-induced hyperalgesia (RIH), matrix metalloproteinase-9 (MMP-9), N-acetyl-cysteine (NAC), dorsal root ganglia (DRG)
Received: December 16, 2016 Accepted: January 27, 2017 Published: February 09, 2017
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.
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