cyprodime and naloxonazine

To investigate the role of opioid μ-receptor subtype in opiate-induced constipation (OIC).. The effect of loperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine (ACh). Then, decrease in muscle tone (relaxation) was characterized after cumulative administration of 0.1-10 μmol/L loperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreatment to compare the changes in loperamide-induced relaxation.. In addition to the delay in intestinal transit, loperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K+ (K(ATP)) channels, and by protein kinase A (PKA) inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate (cAMP).. Loperamide induces intestinal relaxation by activation of opioid μ-2 receptors via the cAMP-PKA pathway to open K(ATP) channels, relates to OIC.

Topics: Acetylcholine; Analgesics, Opioid; Animals; Antidiarrheals; Constipation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Gastrointestinal Transit; Glyburide; Humans; Intestine, Small; Loperamide; Male; Mice; Mice, Inbred BALB C; Morphinans; Muscle Relaxation; Naloxone; Receptors, Opioid, mu

The role of opioid receptors in the regulation of vascular function remains unclear. In the current study, we evaluated the ability of loperamide, a peripheral opioid receptor agonist, to regulate blood pressure in spontaneously hypertensive rats (SHRs) and examined the mechanism(s) by which loperamide exerts its effects.. In male SHRs, mean arterial pressure (MAP) was measured and hemodynamic analysis was recorded. Additionally, the isometric tension of aortic rings isolated from SHRs was determined.. Loperamide dose-dependently decreased MAP in SHRs but not in the normal group of Wistar-Kyoto rats. This reduction of MAP in conscious SHRs was abolished by the selective opioid μ-receptor antagonist cyprodime, but not by naloxonazine, the μ(1)-opioid receptor antagonist. However, cardiac output was not altered by loperamide in anesthetized SHRs. Moreover, loperamide-induced relaxation in isolated aortic rings precontracted with phenylephrine or vasopressin. This relaxation was abolished by cyprodime, but not by naloxonazine. Loperamide-induced relaxation was also attenuated by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. Additionally, vasodilatation by loperamide was reduced by an inhibitor of protein kinase A (PKA) and enhanced by an inhibitor of phosphodiesterases.. We suggest that loperamide can lower MAP in SHRs via μ(2)-opioid receptor-dependent cAMP-PKA pathway that induces vascular relaxation by opening K(ATP) channels.

Topics: Animals; Arteries; Blood Pressure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endothelium; Glyburide; Hemodynamics; Intracellular Signaling Peptides and Proteins; KATP Channels; Loperamide; Male; Morphinans; Naloxone; Phenylephrine; Phosphodiesterase Inhibitors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid, mu; Vasodilation