Oxysophocarpine Ameliorates Carrageenan-induced Inflammatory Pain via Inhibiting Expressions of Prostaglandin E₂ and Cytokines in Mice

Abstract

Oxysophocarpine is an alkaloid extracted from Sophora alopecuroides. We investigated the analgesic effect of oxysophocarpine on carrageenan-induced inflammatory pain in mice, in order to explore its possible mechanisms. Mouse ear swelling tests and carrageenan-induced paw edema tests were used to investigate the effects of oxysophocarpine on inflammatory pain in mice. Morphological changes on inflamed paw sections were measured by hematoxylin-eosin staining. The mRNA and protein expression of extracellular signal-regulated kinase, phosphorylation of extracellular signal-regulated kinase 1/2, cyclooxygenase-2, tumor necrosis factor α, interleukin-1 beta, interleukin-6 and prostaglandin E₂ were investigated by real-time quantitative polymerase chain reaction, immunohistochemistry, western-blot and enzyme-linked immunosorbent assay. In our results, oxysophocarpine shows a significant anti-inflammatory effect in the mouse ear swelling test. Oxysophocarpine also significantly reduced the paw edema volume and improved mechanical allodynia threshold value on carrageenan-induced inflammatory pain, as well as relieved paw tissues inflammatory damage and reduced the numbers of neutrophils in mice. Oxysophocarpine significantly suppressed over-expression of cyclooxygenase-2, tumor necrosis factor α, interleukin-1 beta, interleukin-6 and prostaglandin E₂, and inhibited the over-phosphorylation of extracellular signal-regulated kinase 1/2. Based on these findings we propose that oxysophocarpine attenuates inflammatory pain by suppressing the levels of phosphorylation of extracellular signal-regulated kinase 1/2, cyclooxygenase-2, prostaglandin E₂, tumor necrosis factor α, interleukin-1 beta and interleukin-6.

Key words

Sophora alopecuroides - Leguminosae - oxysophocarpine - inflammation pain - pro-inflammatory cytokines - prostaglandin E₂

^* These authors contributed equally to this work.

• References

• 1 Reinold H, Ahmadi S, Depner UB, Layh B, Heindl C, Hamza M, Pahl A, Brune K, Narumiya S, Müller U, Zeilhofer HU. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Invest 2005; 115: 673-679
• 2 Mifflin KA, Kerr BJ. The transition from acute to chronic pain: understanding how different biological systems interact. Can J Anaesth 2014; 61: 112-122
• 3 Khan S, Shehzad O, Chun J, Kim YS. Mechanism underlying anti-hyperalgesic and anti-allodynic properties of anomalin in both acute and chronic inflammatory pain models in mice through inhibition of NF-κB, MAPKs and CREB signaling cascades. Eur J Pharmacol 2013; 718: 448-458
• 4 Kassuya CA, Ferreira J, Claudino RF, Calixto JB. Intraplantar PGE2 causes nociceptive behaviour and mechanical allodynia: the role of prostanoid E receptors and protein kinases. Br J Pharmacol 2007; 150: 727-737
• 5 Ulmann L, Hirbec H, Rassendren F. P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J 2010; 29: 2290-2300
• 6 Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute antihyperalgesic action of nonsteroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosci 2001; 21: 5847-5853
• 7 Borghi SM, Carvalho TT, Staurengo-Ferrari L, Hohmann MS, Pinge-Filho P, Casagrande R, Verri jr. WA. Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. J Nat Prod 2013; 76: 1141-1149
• 8 Fang JF, Liang Y, Du JY, Fang JQ. Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats. BMC Complement Altern Med 2013; 13: 1-34
• 9 Lee MJ, Jang M, Jung HS, Kim SH, Cho IH. Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation. Mol Pain 2012; 8: 1-40
• 10 Xu ZZ, Zhang L, Liu T, Park JY, Berta T, Yang R, Serhan CN, Ji RR. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat Med 2010; 16: 592-597
• 11 Pulichino AM, Rowland S, Wu T, Clark P, Xu D, Mathieu MC, Riendeau D, Audoly LP. Prostacyclin antagonism reduces pain and inflammation in rodent models of hyperalgesia and chronic arthritis. J Pharmacol Exp Ther 2006; 319: 1043-1050
• 12 Xu T, Li Y, Wang H, Xu Y, Ma L, Sun T, Ma H, Yu J. Oxysophocarpine induces anti-nociception and increases the expression of GABAAα1 receptors in mice. Mol Med Rep 2013; 7: 1819-1825
• 13 Ristoiu V. Contribution of macrophages to peripheral neuropathic pain pathogenesis. Life Sci 2013; 93: 870-881
• 14 Guillot X, Semerano L, Decker P, Falgarone G, Boissier MC. Pain and immunity. Joint Bone Spine 2012; 79: 228-236
• 15 Yosipovitch G, Mills KC, Nattkemper LA, Feneran A, Tey HL, Lowenthal BM, Pearce DJ, Williford PM, Sangueza OP, DʼAgostino jr. RB. Association of pain and itch with depth of invasion and inflammatory cell constitution in skin cancer: results of a large clinicopathologic Study. JAMA Dermatol 2014; 150: 1160-1166
• 16 Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010; 16: 1267-1276
• 17 Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 2011; 50: 600-613
• 18 Choi JI, Koehrn FJ, Sorkin LS. Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn. Mol Pain 2012; 8: 4
• 19 Chou TC. Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia. Br J Pharmacol 2003; 139: 1146-1152
• 20 Sachs D, Cunha FQ, Poole S, Ferreira SH. Tumour necrosis factor-alpha, interleukin-1beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity. Pain 2002; 96: 89-97
• 21 Song X, Zhang W, Wang T, Jiang H, Zhang Z, Fu Y, Yang Z, Cao Y, Zhang N. Geniposide plays an anti-inflammatory role via regulating TLR4 and downstream signaling pathways in lipopolysaccharide-induced mastitis in mice. Inflammation 2014; 37: 1588-1598
• 22 Zarpelon AC, Cunha TM, Alves-Filho JC, Pinto LG, Ferreira SH, McInnes IB, Xu D, Liew FY, Cunha FQ, Verri jr. WA. IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2. Br J Pharmacol 2013; 169: 90-101
• 23 Ren K, Torres R. Role of interleukin-1beta during pain and inflammation. Brain Res Rev 2009; 60: 57-64
• 24 Kulmatycki KM, Jamali F. Drug disease interactions: role of inflammatory mediators in pain and variability in analgesic drug response. J Pharm Pharm Sci 2007; 10: 554-566
• 25 Claudino RF, Kassuya CA, Ferreira J, Calixto JB. Pharmacological and molecular characterization of the mechanisms involved in prostaglandin E2-induced mouse paw edema. J Pharmacol Exp Ther 2006; 318: 611-618
• 26 Schinella G, Neyret E, Cónsole G, Tournier H, Prieto JM, Ríos JL, Giner RM. An aqueous extract of Ilex paraguariensis reduces carrageenan-induced edema and inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase in animal models of inflammation. Planta Med 2014; 80: 961-968
• 27 Leite FC, Ribeiro-Filho J, Costa HF, Salgado PR, Calheiros AS, Carneiro AB, de Almeida RN, Dias Cda S, Bozza PT, Piuvezam MR. Curine, an alkaloid isolated from Chondrodendron platyphyllum inhibits prostaglandin E2 in experimental models of inflammation and pain. Planta Med 2014; 80: 1072-1078
• 28 Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010; 16: 1267-1276
• 29 Dongmo AB, Nguelefack T, Lacaille-Dubois MA. Antinociceptive and anti-inflammatory activities of Acacia pennata wild (Mimosaceae). J Ethnopharmacol 2005; 98: 201-206
• 30 Aquino AB, Cavalcante-Silva LH, Matta CB, Epifânio WA, Aquino PG, Santana AE, Alexandre-Moreira MS, de Araújo-Júnior JX. The antinociceptive and anti-inflammatory activities of Aspidosperma tomentosum (Apocynaceae). ScientificWorldJournal 2013; 2013: 218627
• 31 Chang TN, Deng JS, Chang YC, Lee CY, Jung-Chun L, Lee MM, Peng WH, Huang SS, Huang GJ. Ameliorative effects of scopoletin from Crossostephium chinensis against inflammation pain and its mechanisms in mice. Evid Based Complement Alternat Med 2012; 2012: 595-603