Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Abstract

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. IntroductionBenign prostatic hyperplasia (Bph) occurs frequently in older men and is associated with lower urinary tract symptoms causing obstruction of the proximal urethra and urinary flow disturbances (1). In clinics, medical treatments for BPH include widely used α-1 antagonists and 5-α-reductase inhibitors. however, the side effects, such as postural hypotension, erectile dysfunction and ejaculatory difficulty, disturb the quality of life of these patients (2,3). therefore, development of a more effective therapy for the treatment of Bph is urgent and necessary.loperamide is widely used in the clinic for a variety of diarrheal syndromes, including acute and nonspecific (infectious) diarrhea (4,5). Recently, we identified opioid µ-receptor expression in rat prostates, and prostatic relaxation was induced by the activation of opioid µ-receptors using loperamide (6). loperamide was introduced as a peripheral agonist of opioid µ-receptors with poor ability to penetrate the bloodbrain barrier (7,8). Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10). (+)-tramadol was found to activate peripheral opioid µ-receptors to exhibit a concentration-dependent relaxation of aorta (11). Basically, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 opioid receptors (12). however, activation of opioid µ-1 receptors ...

Alteration of Loperamide-Induced Prostate Relaxation in High-Fat Diet-Fed Rats

“…There are two principal signal transduction pathways involving the G protein-coupled receptors: the cyclic AMP (cAMP) signal pathway and the phosphatidylinositol signal pathway. A prior study showed that the mechanism for loperamide-induced prostatic relaxation was mediated through cAMP-protein kinase A (PKA) pathway to open K ATP channels [ 16 ]. The activation of K ATP channels causes hyperpolarization of cell membrane and consequently smooth muscle relaxation.…”

“…The method we used for rat prostate strip contractile response study had been previously reported [ 2 , 10 ]. The rat was sacrificed by decapitation under anesthesia with intraperitoneal pentobarbital (50 mg/kg).…”