Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse.

نویسندگان

  • Guijun Fei
  • Kirsten Raehal
  • Sumei Liu
  • Mei-Hua Qu
  • Xiaohong Sun
  • Guo-Du Wang
  • Xi-Yu Wang
  • Yun Xia
  • Cullen L Schmid
  • Laura M Bohn
  • Jackie D Wood
چکیده

Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

A comparative study on the effects of new opioid compounds and morphine on the contractility of guinea pig ileum and mouse vas deferens

Considering the clinical significance of opioids, especially their application for the treatment of severe painful conditions including cancer pain and the requirement for the synthesis of more specific drugs with lower side effects, this study was conducted to perform a preliminary investigation on six newly developed opioid drugs. Our aim was to introduce drugs that act selectively on the opi...

متن کامل

Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

BACKGROUND AND AIMS Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist pepti...

متن کامل

Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon.

Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current (Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1-3...

متن کامل

Inhibitory Effect of Ruta graveolens L. Extract on Guinea Pig Liver and Bovine Milk Xanthine Oxidase

      Flavonoids could serve as potent inhibitors of xanthine oxidase (XO). In the present study, the effects of Ruta graveolens L. extract and its major isolated flavonoids, quercetin and rutin, on guinea pig liver XO have been investigated. The inhibitory effects of R. graveolens, quercetin and its glycoside form, rutin, were assayed spectrophotometrically. R. graveolens...

متن کامل

Onion, a Potent Inhibitor of Xantine Oxidase

Onion (Allium Cepa) contains high levels of flavonoids. Although there are many studies indicating the inhibitory effects of flavonoids on xanthine oxidase, there is no report on the effect of onion on this enzyme. Therefore, in the present study, the inhibitory effects of onion on xanthine oxidase are investigated. Fresh filtered juice of onion was prepared and its inhibitory effect on guine...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • The Journal of pharmacology and experimental therapeutics

دوره 334 1  شماره 

صفحات  -

تاریخ انتشار 2010