Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we -explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide -dismutase activity (p < 0.01) compared with control and -incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.

Keywords:
Betulinic acid, Remifentanil-induced hyperalgesia, Oxidative stress, Matrix metalloproteinase-9, Inflammation
1.
Fletcher D, Martinez V: Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 2014; 112: 991–1004.
2.
Heinl C, Drdla-Schutting R, Xanthos DN, Sandkuhler J: Distinct mechanisms underlying pronociceptive effects of opioids. J Neurosci 2011; 31: 16748–16756.
3.
Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L: A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14: 145–161.
4.
Xia WS, Peng YN, Tang LH, Jiang LS, Yu LN, Zhou XL, Zhang FJ, Yan M: Spinal ephrinb/ephb signalling contributed to remifentanil-induced hyperalgesia via NMDA receptor. Eur J Pain 2014; 18: 1231–1239.
5.
Liu Y, Ni Y, Zhang W, Sun YE, Ma Z, Gu X: N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia. Oncotarget 2017; 8: 16988–17001.
6.
Shu RC, Zhang LL, Wang CY, Li N, Wang HY, Xie KL, Yu YH, Wang GL: Spinal peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via enhancement of divalent metal transporter 1 without iron-responsive element-mediated iron accumulation in rats. Anesthesiology 2015; 122: 908–920.
7.
Ye L, Xiao L, Yang SY, Duan JJ, Chen Y, Cui Y, Chen Y: Cathepsin s in the spinal microglia contributes to remifentanil-induced hyperalgesia in rats. Neuroscience 2017; 344: 265–275.
8.
Berta T, Liu T, Liu YC, Xu ZZ, Ji RR: Acute morphine activates satellite glial cells and up-regulates IL-1β dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain 2012; 8: 18.
9.
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR: Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 2008; 14: 331–336.
10.
Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ: Matrix metalloproteinases and neurotrauma: Evolving roles in injury and reparative processes. Neuroscientist 2010; 16: 156–170.
11.
Galis ZS, Asanuma K, Godin D, Meng X: N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells: new target for antioxidant therapy? Circulation 1998; 97: 2445–2453.
12.
Oyebanji BO, Saba AB, Oridupa OA: Studies on the anti-inflammatory, analgesic and antipyrexic activities of betulinic acid derived from tetracera potatoria. Afr J Tradit Complement Altern Med 2014; 11: 30–33.
13.
Yogeeswari P, Sriram D: Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 2005; 12: 657–666.
14.
Kalra J, Lingaraju MC, Mathesh K, Kumar D, Parida S, Singh TU, Sharma AK, Kumar D, Tandan SK: Betulinic acid alleviates dextran sulfate sodium-induced colitis and visceral pain in mice. Naunyn Schmiedebergs Arch Pharmacol 2018; 391: 285–297.
15.
Brennan TJ, Vandermeulen EP, Gebhart GF: Characterization of a rat model of incisional pain. Pain 1996; 64: 493–501.
16.
Gu X, Wu X, Liu Y, Cui S, Ma Z: Tyrosine phosphorylation of the N-methyl-D-aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine. Mol Pain 2009; 5: 76.
17.
Zhang L, Shu R, Wang C, Wang H, Li N, Wang G: Hydrogen-rich saline controls remifentanil-induced hypernociception and NMDA receptor NR1 subunit membrane trafficking through GSK-3β in the DRG in rats. Brain Res Bull 2014; 106: 47–55.
18.
Sun Y, Zhang W, Liu Y, Liu X, Ma Z, Gu X: Intrathecal injection of jwh015 attenuates remifentanil-induced postoperative hyperalgesia by inhibiting activation of spinal glia in a rat model. Anesth Analg 2014; 118: 841–853.
19.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55–63.
20.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77–88.
21.
Tarry-Adkins JL, Martin-Gronert MS, Fernandez-Twinn DS, Hargreaves I, Alfaradhi MZ, Land JM, Aiken CE, Ozanne SE: Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart. FASEB J 2013; 27: 379–390.
22.
Zhang L, Shu R, Wang H, Yu Y, Wang C, Yang M, Wang M, Wang G: Hydrogen-rich saline prevents remifentanil-induced hyperalgesia and inhibits mnsod nitration via regulation of NR2B-containing nmda receptor in rats. Neuroscience 2014; 280: 171–180.
23.
Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ: Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J Med Chem 1991; 34: 2202–2208.
24.
Trescot AM, Helm S, Hansen H, Benyamin R, Glaser SE, Adlaka R, Patel S, Manchikanti L: Opioids in the management of chronic non-cancer pain: an update of american society of the interventional pain physicians’ (asipp) guidelines. Pain Physician 2008; 11:S5–S62.
25.
Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R: Opioid complications and side effects. Pain Physician 2008; 11:S105–S120.
26.
Kim SH, Stoicea N, Soghomonyan S, Bergese SD: Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review. Am J Ther 2015; 22:e62–e74.
27.
Ye L, Xiao L, Bai X, Yang SY, Li Y, Chen Y, Cui Y, Chen Y: Spinal mitochondrial-derived ros contributes to remifentanil-induced postoperative hyperalgesia via modulating nmda receptor in rats. Neurosci Lett 2016; 634: 79–86.
28.
Nader MA, Baraka HN: Effect of betulinic acid on neutrophil recruitment and inflammatory mediator expression in lipopolysaccharide-induced lung inflammation in rats. Eur J Pharm Sci 2012; 46: 106–113.
29.
Doyle T, Esposito E, Bryant L, Cuzzocrea S, Salvemini D: Nadph-oxidase 2 activation promotes opioid-induced antinociceptive tolerance in mice. Neuroscience 2013; 241: 1–9.
30.
Muscoli C, Cuzzocrea S, Ndengele MM, Mollace V, Porreca F, Fabrizi F, Esposito E, Masini E, Matuschak GM, Salvemini D: Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. J Clin Invest 2007; 117: 3530–3539.
31.
Szabo C, Ischiropoulos H, Radi R: Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 2007; 6: 662–680.
32.
Mert T, Oksuz H, Tugtag B, Kilinc M, Senoglu N, Bilgin R: Modulating actions of nmda receptors on pronociceptive effects of locally injected remifentanil in diabetic rats. Pharmacol Rep 2014; 66: 1065–1072.
33.
Chu C, Levine E, Gear RW, Bogen O, Levine JD: Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia. Pain 2011; 152: 1832–1837.
34.
Muscoli C, Mollace V, Wheatley J, Masini E, Ndengele M, Wang ZQ, Salvemini D: Superoxide-mediated nitration of spinal manganese superoxide dismutase: a novel pathway in N-methyl-D-aspartate-mediated hyperalgesia. Pain 2004; 111: 96–103.
35.
Salvemini D, Little JW, Doyle T, Neumann WL: Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med 2011; 51: 951–966.
36.
Ndengele MM, Cuzzocrea S, Masini E, Vinci MC, Esposito E, Muscoli C, Petrusca DN, Mollace V, Mazzon E, Li D, Petrache I, Matuschak GM, Salvemini D: Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation. J Pharmacol Exp Ther 2009; 329: 64–75.
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