Role of ERK1/2 activation on itch sensation induced by bradykinin B1 activation in inflamed skin

Chen,Yuanzhen; Jiang,Shuyan; Liu,Yuying; Xiong,Jialing; Liang,Jiexian; Ji,Wenjin

doi:10.3892/etm.2016.3426

Role of ERK1/2 activation on itch sensation induced by bradykinin B1 activation in inflamed skin

Authors:
- Yuanzhen Chen
- Shuyan Jiang
- Yuying Liu
- Jialing Xiong
- Jiexian Liang
- Wenjin Ji
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Affiliations: Postgraduate Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Anesthesiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
Published online on: June 6, 2016 https://doi.org/10.3892/etm.2016.3426
Pages: 627-632
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has previously been demonstrated that bradykinin receptor B1 (B1R) agonists evoke an itch-related scratching response in inflamed skin via the B1 receptor; however, the mechanisms responsible for this abnormal itch sensation remain unclear. Therefore, the present study utilized a complete Freund's adjuvant (CFA)-induced mouse model of inflammation to elucidate the mechanisms responsible. Over a period of 30 min, scratching behavior was quantified by the number of hind limb scratches of the area surrounding the drug injection site on the neck. Furthermore, western blot analysis was used to investigate the potential role of extracellular signal‑regulated kinase (ERK) 1/2 signaling as a mediator of itch in CFA‑treated mice. The results demonstrated that CFA‑induced inflammation at the back of the neck is associated with sustained enhancement of ERK1/2 activation in the spinal cord. Moreover, B1R agonist treatment resulted in increased expression of phosphorylated ERK1/2 in the spinal cord, which peaked at 45 min. Consistent with these findings, inhibition of either mitogen‑activated protein/ERK kinase or ERK1/2, as well as inhibition of ERK1/2 activation following inflammation, attenuated B1 receptor‑mediated scratching responses to a greater extent, as compared with control mice. Collectively, the results of the present study indicated that enhanced and persistent ERK1/2 activation in the spinal cord may be required to induce a scratching response to B1R agonists following CFA-induced inflammation.

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1	Ständer S and Schmelz M: Chronic itch and pain-Similarities and differences. Eur J Pain. 10:4732006. View Article : Google Scholar : PubMed/NCBI
2	Ma C, Nie H, Gu Q, Sikand P and Lamotte RH: In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol. 107:357–363. 2012. View Article : Google Scholar : PubMed/NCBI
3	Liu T and Ji R: New insights into the mechanisms of itch: Are pain and itch controlled by distinct mechanisms? Pflügers Arch. 465:1671–1685. 2013. View Article : Google Scholar
4	Davidson S and Giesler GJ: The multiple pathways for itch and their interactions with pain. Trends Neurosci. 33:550–558. 2010. View Article : Google Scholar : PubMed/NCBI
5	Hosogi M, Schmelz M, Miyachi Y and Ikoma A: Bradykinin is a potent pruritogen in atopic dermatitis: A switch from pain to itch. Pain. 126:16–23. 2006. View Article : Google Scholar : PubMed/NCBI
6	Sikand P, Shimada SG, Green BG and LaMotte RH: Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain. 144:66–75. 2009. View Article : Google Scholar : PubMed/NCBI
7	Liang J, Xiao G and Ji W: Capsaicin induces reflex scratching in inflamed skin. Pharmacology. 88:82–87. 2011. View Article : Google Scholar : PubMed/NCBI
8	Liang J, He Y and Ji W: Bradykinin-evoked scratching responses in complete Freund's adjuvant-inflamed skin through activation of B1 receptor. Exp Biol Med (Maywood). 237:318–326. 2012. View Article : Google Scholar : PubMed/NCBI
9	Feng J, Chen Y, Xiong J, Chen X, Liang J and Ji W: The kinin B1 receptor mediates alloknesis in a murine model of inflammation. Neurosci Lett. 560:31–35. 2014. View Article : Google Scholar : PubMed/NCBI
10	Fang JQ, Fang JF, Liang Y and Du JY: Electroacupuncture mediates extracellular signal-regulated kinase 1/2 pathways in the spinal cord of rats with inflammatory pain. BMC Complement Altern Med. 14:2852014. View Article : Google Scholar : PubMed/NCBI
11	Ji RR, Befort K, Brenner GJ and Woolf CJ: ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci. 22:478–485. 2002.PubMed/NCBI
12	Zhang L, Jiang GY, Song NJ, Huang Y, Chen JY, Wang QX and Ding YQ: Extracellular signal-regulated kinase (ERK) activation is required for itch sensation in the spinal cord. Mol Brain. 7:252014. View Article : Google Scholar : PubMed/NCBI
13	Kido-Nakahara M, Buddenkotte J, Kempkes C, Ikoma A, Cevikbas F, Akiyama T, Nunes F, Seeliger S, Hasdemir B, Mess C, et al: Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. J Clin Invest. 124:2683–2695. 2014. View Article : Google Scholar : PubMed/NCBI
14	Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S, Kim S, Liu XY, Barry DM, Wan L, Liu ZC, et al: Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest. 123:4769–4780. 2013. View Article : Google Scholar : PubMed/NCBI
15	Pearson G, Robinson F, Gibson Beers T, Xu BE, Karandikar M, Berman K and Cobb MH: Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr Rev. 22:153–183. 2001. View Article : Google Scholar : PubMed/NCBI
16	Shaul YD and Seger R: The MEK/ERK cascade: From signaling specificity to diverse functions. Biochim Biophys Acta. 1773:1213–1226. 2007. View Article : Google Scholar : PubMed/NCBI
17	Seino D, Tokunaga A, Tachibana T, Yoshiya S, Dai Y, Obata K, Yamanaka H, Kobayashi K and Noguchi K: The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint. Pain. 123:193–203. 2006. View Article : Google Scholar : PubMed/NCBI
18	Obata K and Noguchi K: MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 74:2643–2653. 2004. View Article : Google Scholar : PubMed/NCBI
19	Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A and Noguchi K: Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci. 20:2881–2895. 2004. View Article : Google Scholar : PubMed/NCBI
20	Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A and Noguchi K: Activation of extracellular signal-regulated protein kinase in the dorsal root ganglion following inflammation near the nerve cell body. Neuroscience. 126:1011–1021. 2004. View Article : Google Scholar : PubMed/NCBI
21	Obata K, Yamanaka H, Dai Y, Tachibana T, Fukuoka T, Tokunaga A, Yoshikawa H and Noguchi K: Differential activation of extracellular signal-regulated protein kinase in primary afferent neurons regulates brain-derived neurotrophic factor expression after peripheral inflammation and nerve injury. J Neurosci. 23:4117–4126. 2003.PubMed/NCBI
22	Zhang X, Zhang H, Shao H, Xue Q and Yu B: ERK MAP kinase activation in spinal cord regulates phosphorylation of cdk5 at serine 159 and contributes to peripheral inflammation induced pain/hypersensitivity. PLoS One. 9:e877882014. View Article : Google Scholar : PubMed/NCBI
23	Zhang YL, Shi XD, Fu D, Xu JM and Dai RP: Activation of spinal ERK1/2 contributes to mechanical allodynia in a rat model of postoperative pain. Molecular Medicine Reports. 7:1661–1665. 2013.PubMed/NCBI
24	Sanna MD, Mello T, Ghelardini C and Galeotti N: Inhibition of spinal ERK1/2-c-JUN signaling pathway counteracts the development of low doses morphine-induced hyperalgesia. Eur J Pharmacol. 764:271–277. 2015. View Article : Google Scholar : PubMed/NCBI
25	Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, et al: A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 133:448–460. 2014. View Article : Google Scholar : PubMed/NCBI
26	Ji RR, Baba H, Brenner GJ and Woolf CJ: Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 2:1114–1119. 1999. View Article : Google Scholar : PubMed/NCBI
27	Karim F, Hu HJ, Adwanikar H, Kaplan D and Gereau RW IV: Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK). Mol Pain. 2:22006. View Article : Google Scholar : PubMed/NCBI
28	Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, et al: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 273:18623–18632. 1998. View Article : Google Scholar : PubMed/NCBI
29	Song XS, Cao JL, Xu YB, He JH, Zhang LC and Zeng YM: Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats. Acta Pharmacol Sin. 26:789–798. 2005. View Article : Google Scholar : PubMed/NCBI
30	Kilstein Y, Nowak W, Errasti AE, Feás AA, Armesto AR, Pelorosso FG and Rothlin RP: Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins. J Pharmacol Exp Ther. 357:114–124. 2016. View Article : Google Scholar : PubMed/NCBI
31	Adwanikar H, Karim F and Gereau RW IV: Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation. Pain. 111:125–135. 2004. View Article : Google Scholar : PubMed/NCBI
32	Gao YJ and Ji RR: Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: Involvement of spinal astrocytes and JNK signaling in touch-evoked central sensitization and mechanical allodynia. J Neurochem. 115:505–514. 2010. View Article : Google Scholar : PubMed/NCBI
33	Xu YM, Wang XT, Zhang ZY, Suo ZW, Yang X and Hu XD: Noradrenergic α2 receptor attenuated inflammatory pain through STEP61/ERK signalling. Eur J Pain. 19:1298–1307. 2015. View Article : Google Scholar : PubMed/NCBI
34	Ferreira J, Campos MM, Pesquero JB, Araujo RC, Bader M and Calixto JB: Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice. Neuropharmacology. 41:1006–1012. 2001. View Article : Google Scholar : PubMed/NCBI
35	Luo MC, Chen Q, Ossipov MH, Rankin DR, Porreca F and Lai J: Spinal dynorphin and bradykinin receptors maintain inflammatory hyperalgesia. J Pain. 9:1096–1105. 2008. View Article : Google Scholar : PubMed/NCBI
36	Larrivee JF, Bachvarov DR, Houle F, Landry J, Huot J and Marceau F: Role of the mitogen-activated protein kinases in the expression of the kinin B1 receptors induced by tissue injury. J Immunol. 160:1419–1426. 1998.PubMed/NCBI
37	Ehrenfeld P, Matus CE, Pavicic F, Toledo C, Nualart F, Gonzalez CB, Burgos RA, Bhoola KD and Figueroa CD: Kinin B1receptor activation turns on exocytosis of matrix metalloprotease-9 and myeloperoxidase in human neutrophils: Involvement of mitogen-activated protein kinase family. J Leukoc Biol. 86:1179–1189. 2009. View Article : Google Scholar : PubMed/NCBI
38	Zhang Y, Adner M and Cardell LO: Up-regulation of bradykinin receptors in a murine in-vitro model of chronic airway inflammation. Eur J Pharmacol. 489:117–126. 2004. View Article : Google Scholar : PubMed/NCBI
39	Bryborn M, Adner M and Cardell LO: Interleukin-4 increases murine airway response to kinins, via up-regulation of bradykinin B1-receptors and altered signalling along mitogen-activated protein kinase pathways. Clin Exp Allergy. 34:1291–1298. 2004. View Article : Google Scholar : PubMed/NCBI