Propofol inhibits expression of angiotensin II receptor type 2 in dorsal root ganglion neurons

Pan,Bingbing; Cheng,Zhigang; Kong,Gaoyin; Song,Zongbin; Wang,Yunjiao; Wei,Lai; Xiao,Dan; Zhao,Yuan; Guo,Qulian

doi:10.3892/etm.2017.4040

Propofol inhibits expression of angiotensin II receptor type 2 in dorsal root ganglion neurons

Authors:
- Bingbing Pan
- Zhigang Cheng
- Gaoyin Kong
- Zongbin Song
- Yunjiao Wang
- Lai Wei
- Dan Xiao
- Yuan Zhao
- Qulian Guo
View Affiliations

Affiliations: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China, Department of Anesthesiology, Hunan Provincial People's Hospital, Changsha, Hunan 410001, P.R. China
Published online on: January 12, 2017 https://doi.org/10.3892/etm.2017.4040
Pages: 867-872
Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The renin‑angiotensin system (RAS) is involved in nociception and has functions in the cardiovascular system. The primary role of the RAS is to mediate the effect of angiotensin II (Ang II) through Ang II receptor type 2 (AT2). Due to this, AT2 has become a novel therapeutic target for the relief of peripheral neuropathic pain in humans. As it is one of the most popular induction agents of general anesthesia, propofol also exerts peripheral antinociceptive effects. The present study assessed the effect of propofol on the expression of AT2 in cultured dorsal root ganglion (DRG) neurons. The results indicate that propofol decreases AT2 mRNA expression in a statistically significant dose‑ and time‑dependent manner (P<0.05). This resulted in a marked decrease in AT2 protein expression and the density of Ang II‑binding AT2 on the cell membrane of DRG neurons. The effect of propofol was reversed by LY294002, a phosphatidylinositol 3‑kinase (PI3K) inhibitor. Although propofol exhibited no significant effect on AT2 gene promoter activity, it significantly decreased the stability of AT2 mRNA (P<0.05). However, this effect was reversed by LY294002. In addition, propofol increased PI3K activity in a concentration‑dependent manner in DRG neurons. In conclusion, to the best of our knowledge, the current study provides the first evidence suggesting that propofol inhibits the expression of AT2 in DRG neurons by decreasing the stability of AT2 mRNA through a PI3K‑dependent mechanism. The present study provides novel insights into the mechanisms of the peripheral antinociceptive action of propofol and suggests a potential means of regulating Ang II/AT2 signaling in the peripheral nervous system.

View Figures

View References

1	Pelegrini-da-Silva A, Martins AR and Prado WA: A new role for the renin-angiotensin system in the rat periaqueductal gray matter: Angiotensin receptor-mediated modulation of nociception. Neuroscience. 132:453–463. 2005. View Article : Google Scholar : PubMed/NCBI
2	Sakagawa T, Okuyama S, Kawashima N, Hozumi S, Nakagawasai O, Tadano T, Kisara K, Ichiki T and Inagami T: Pain threshold, learning and formation of brain edema in mice lacking the angiotensin II type 2 receptor. Life Sci. 67:2577–2585. 2000. View Article : Google Scholar : PubMed/NCBI
3	Pavel J, Tang H, Brimijoin S, Moughamian A, Nishioku T, Benicky J and Saavedra JM: Expression and transport of Angiotensin II AT1 receptors in spinal cord, dorsal root ganglia and sciatic nerve of the rat. Brain Res. 1246:111–122. 2008. View Article : Google Scholar : PubMed/NCBI
4	Anand U, Facer P, Yiangou Y, Sinisi M, Fox M, McCarthy T, Bountra C, Korchev YE and Anand P: Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. Eur J Pain. 17:1012–1026. 2013. View Article : Google Scholar : PubMed/NCBI
5	Smith MT, Wyse BD and Edwards SR: Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: Comparative pharmacokinetics, radioligand binding, and efficacy in rats. Pain Med. 14:692–705. 2013. View Article : Google Scholar : PubMed/NCBI
6	Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, et al: EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: A randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet. 383:1637–1647. 2014. View Article : Google Scholar : PubMed/NCBI
7	Marik PE: Propofol: An immunomodulating agent. Pharmacotherapy. 25:28S–33S. 2005. View Article : Google Scholar : PubMed/NCBI
8	Cao L, Xun J, Jiang X and Tan R: Propofol up-regulates Mas receptor expression in dorsal root ganglion neurons. Pharmazie. 68:677–680. 2013.PubMed/NCBI
9	Takechi K, Carstens MI, Klein AH and Carstens E: The antinociceptive and antihyperalgesic effects of topical propofol on dorsal horn neurons in the rat. Anesth Analg. 116:932–938. 2013. View Article : Google Scholar : PubMed/NCBI
10	Ichiki T, Kambayashi Y and Inagami T: Transcription of the rat angiotensin II type 2-receptor gene. Biochem Biophys Res Commun. 222:566–571. 1996. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-(Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Cao CM, Zhang Y, Weisleder N, Ferrante C, Wang X, Lv F, Zhang Y, Song R, Hwang M, Jin L, et al: MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation. 121:2565–2574. 2010. View Article : Google Scholar : PubMed/NCBI
13	Fos C, Salles A, Lang V, Carrette F, Audebert S, Pastor S, Ghiotto M, Olive D, Bismuth G and Nunès JA: ICOS ligation recruits the p50alpha PI3K regulatory subunit to the immunological synapse. J Immunol. 181:1969–1977. 2008. View Article : Google Scholar : PubMed/NCBI
14	Yang Y, Wu H, Yan JQ, Song ZB and Guo QL: Tumor necrosis factor-α inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via β-catenin signaling. Neuroscience. 248:383–391. 2013. View Article : Google Scholar : PubMed/NCBI
15	Verdonk K, Danser AH and van Esch JH: Angiotensin II type 2 receptor agonists: Where should they be applied? Expert Opin Investig Drugs. 21:501–513. 2012. View Article : Google Scholar : PubMed/NCBI
16	Paul M, Mehr A Poyan and Kreutz R: Physiology of local renin-angiotensin systems. Physiol Rev. 86:747–803. 2006. View Article : Google Scholar : PubMed/NCBI
17	Yamakura T, Bertaccini E, Trudell JR and Harris RA: Anesthetics and ion channels: Molecular models and sites of action. Annu Rev Pharmacol Toxicol. 41:23–51. 2001. View Article : Google Scholar : PubMed/NCBI
18	Bandschapp O, Filitz J, Ihmsen H, Berset A, Urwyler A, Koppert W and Ruppen W: Analgesic and antihyperalgesic properties of propofol in a human pain model. Anesthesiology. 113:421–428. 2010. View Article : Google Scholar : PubMed/NCBI
19	Hand R Jr, Riley GP, Nick ML, Shott S and Faut-Callahan M: The analgesic effects of subhypnotic doses of propofol in human volunteers with experimentally induced tourniquet pain. AANA J. 69:466–470. 2001.PubMed/NCBI