Prostatic Relaxation Induced by Loperamide is Mediated Through Activation of Opioid μ-2 Receptors in Vitro

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2012 Sep 15

PMID 22977498

Citations 1

Authors

Chih-Cheng Lu

Hsien-Hui Chung

Juei-Tang Cheng

Affiliations

Soon will be listed here.

Abstract

The merit of opioid μ-receptor activation in the improvement of benign prostatic hyperplasia (BPH) remains obscure. In the present study, we used loperamide to identify the subtype of opioid μ-receptors involved in prostatic relaxation and investigate the possible mechanism of this relaxation. Prostate strips were isolated from 12-week-old male Wistar rats for identification of isometric tension. The prostate strips were precontracted with either 1 μmol/l phenylephrine or 50 mmol/l KCl. The decrease in muscle tone (relaxation) was then characterized after cumulative administration of loperamide (0.1 to 10 μmol/l) into the organ bath for the concentration-dependent study. Pretreatment with specific blockers or antagonists was carried out to compare the changes in loperamide-induced relaxation. Loperamide produced a marked relaxation in the isolated prostates precontracted with phenylephrine or KCl in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but was not modified by naloxonazine at a dose sufficient to block the opioid μ-1 receptors. Treatment with an agonist for opioid μ-1 receptors also failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K(+) channels. In addition, this action of loperamide was abolished by protein kinase A (PKA) inhibitor and enhanced by the inhibitor of phosphodiesterase for cyclic AMP (cAMP). Our results suggest that loperamide induces prostatic relaxation through activation of opioid μ-2 receptors via the cAMP-PKA pathway to open ATP-sensitive K(+) channels.

Citing Articles

Alteration of loperamide-induced prostate relaxation in high-fat diet-fed rats.

Hsu S, Chung H, Chen I, Tong Y ScientificWorldJournal. 2014; 2014:517836.

PMID: 25506071 PMC: 4258308. DOI: 10.1155/2014/517836.

References

Quayle J, Standen N . KATP channels in vascular smooth muscle. Cardiovasc Res. 1994; 28(6):797-804. DOI: 10.1093/cvr/28.6.797. View

Yaksh T . Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist--loperamide. Anesthesiology. 1999; 90(1):225-34. DOI: 10.1097/00000542-199901000-00029. View

Ozdem S, Batu O, Tayfun F, Yalcin O, Meiselman H, Baskurt O . The effect of morphine in rat small mesenteric arteries. Vascul Pharmacol. 2005; 43(1):56-61. DOI: 10.1016/j.vph.2005.04.001. View

Roehrborn C, Marks L, Fenter T, Freedman S, Tuttle J, Gittleman M . Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology. 2004; 63(4):709-15. DOI: 10.1016/j.urology.2004.01.001. View

Abdul M, Hoosein N . Reduced Kv1.3 potassium channel expression in human prostate cancer. J Membr Biol. 2007; 214(2):99-102. DOI: 10.1007/s00232-006-0065-7. View

Stefano G, Hartman A, Bilfinger T, Magazine H, Liu Y, Casares F . Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem. 1995; 270(51):30290-3. DOI: 10.1074/jbc.270.51.30290. View

Teramoto N, Yunoki T, Ikawa S, Takano N, Tanaka K, Seki N . The involvement of L-type Ca(2+) channels in the relaxant effects of the ATP-sensitive K(+) channel opener ZD6169 on pig urethral smooth muscle. Br J Pharmacol. 2001; 134(7):1505-15. PMC: 1573091. DOI: 10.1038/sj.bjp.0704408. View

Mannhold R . KATP channel openers: structure-activity relationships and therapeutic potential. Med Res Rev. 2004; 24(2):213-66. DOI: 10.1002/med.10060. View

Raimundo J, Sudo R, Pontes L, Antunes F, Trachez M, Zapata-Sudo G . In vitro and in vivo vasodilator activity of racemic tramadol and its enantiomers in Wistar rats. Eur J Pharmacol. 2005; 530(1-2):117-23. DOI: 10.1016/j.ejphar.2005.11.028. View

10.

Cadet P . Mu opiate receptor subtypes. Med Sci Monit. 2004; 10(6):MS28-32. View

11.

Bova S, Trevisi L, Cima L, Luciani S, Golovina V, Cargnelli G . Signaling mechanisms for the selective vasoconstrictor effect of norbormide on the rat small arteries. J Pharmacol Exp Ther. 2001; 296(2):458-63. View

12.

Yang P, Lee J, Tsao C, Wu H, Cheng J . Stimulatory effect of stevioside on peripheral mu opioid receptors in animals. Neurosci Lett. 2009; 454(1):72-5. DOI: 10.1016/j.neulet.2009.02.055. View

13.

Wong K, Chan P, Yang H, Hsu F, Liu I, Cheng Y . Isosteviol acts on potassium channels to relax isolated aortic strips of Wistar rat. Life Sci. 2004; 74(19):2379-87. DOI: 10.1016/j.lfs.2003.09.065. View

14.

Oh S, Kim K, Chung Y, Hong E, Shin S, Kim S . Ion-channel currents of smooth muscle cells isolated from the prostate of guinea-pig. BJU Int. 2003; 92(9):1022-30. DOI: 10.1111/j.1464-410x.2003.04510.x. View

15.

Chen J, Smith E, Cahill M, Cohen R, Fishman J . The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci. 1993; 52(4):389-96. DOI: 10.1016/0024-3205(93)90152-s. View

16.

Matsumoto K, Hatori Y, Murayama T, Tashima K, Wongseripipatana S, Misawa K . Involvement of mu-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa. Eur J Pharmacol. 2006; 549(1-3):63-70. DOI: 10.1016/j.ejphar.2006.08.013. View

17.

Tiwari A, Krishna N, Nanda K, Chugh A . Benign prostatic hyperplasia: an insight into current investigational medical therapies. Expert Opin Investig Drugs. 2005; 14(11):1359-72. DOI: 10.1517/13543784.14.11.1359. View

18.

Teramoto N . [Molecular and electrophysiological investigation of ATP-sensitive K+ channels in lower urinary tract function: the aims for clinical treatment of unstable detrusor]. Nihon Yakurigaku Zasshi. 2003; 121(5):317-24. DOI: 10.1254/fpj.121.317. View

19.

Corazziari E . Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol. 1999; 13 Suppl A:71A-75A. DOI: 10.1155/1999/598659. View

20.

Liu I, Liou S, Chen W, Chen P, Cheng J . Signals in the activation of opioid mu-receptors by loperamide to enhance glucose uptake into cultured C2C12 cells. Horm Metab Res. 2004; 36(4):210-4. DOI: 10.1055/s-2004-814449. View