Lubiprostone Reverses the Inhibitory Action of Morphine on Intestinal Secretion in Guinea Pig and Mouse

Fei, Guijun; Raehal, Kirsten M.; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xiyu; Xia, Yun; Schmid, Cullen L.; Bohn, Laura M.; Wood, Jackie D.

doi:10.1124/jpet.110.166116

Cited by 42 publications

(43 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The associated delay in colonic transit increases the duration for water absorption. Opioid-dependent hyperpolarization of submucosal neurons leads to reduced secretomotor activity, fur-ther contributing to constipation (13). However, despite the clear physiological role, established value as a therapeutic target and role in mediating the adverse side effects of opiate analgesics on the bowel, surprisingly little is known about the distribution of opioid receptors in the enteric nervous system.…”

Section: This Article Provides a Detailed Characterization Of The -Opmentioning

confidence: 99%

Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

Lay

Carbone

DiCello

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Lay J, Carbone SE, DiCello JJ, Bunnett NW, Canals M, Poole DP. Distribution and trafficking of the -opioid receptor in enteric neurons of the guinea pig. Am J Physiol Gastrointest Liver Physiol 311: G252-G266, 2016. First published June 30, 2016 doi:10.1152/ajpgi.00184.2016.-The -opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons. In the stomach MOR was mainly localized to nitrergic neurons (ϳ88%), with some overlap with neuropeptide Y (NPY) and no expression by cholinergic neurons. These neurons are likely to have inhibitory motor and secretomotor functions. MOR was restricted to noncholinergic secretomotor neurons (VIP-positive) of the ileum and distal colon submucosal plexus. MOR was mainly detected in nitrergic neurons of the colon (nitric oxide synthase positive, 87%), with some overlap with choline acetyltransferase (ChAT) OPIATES HAVE BEEN USED FOR millennia for their analgesic properties and continue to be routinely used for the treatment of moderate to severe pain. Although opiate analgesics are effective, their use is associated with opioid-induced bowel dysfunction (OBD), a collection of on-target side effects that grossly impact gastrointestinal tract function. OBD can severely limit the use of opiates to treat pain, reducing patient quality of life and compliance, with intractable constipation the most significant problem (28).The direct inhibitory actions of opiates on the isolated colon were first demonstrated nearly a century ago by Trendelenburg. It is now established that opioids and opiates mediate their effects through actions at the ␦-, -, and -opioid G proteincoupled receptors (DOR, KOR, and MOR). These receptors are activated by over 20 endogenous opioid peptides that are generated by differential processing and cleavage of larger precursors, many of which are expressed within the gut (63). Endogenous opioid peptides, including endorphins, enkephalins, and dynorphins, are important regulators of gastrointestinal function and have dampening effects on motility and secretomotor function (70). Opiates, including morphine, mediate their effects on the gut through activation of the MOR expressed by enteric neurons, as demonstrated by mechanistic studies using selective MOR-targeting drugs and oprm1 Ϫ/Ϫ mice (reviewed by Refs. 52,70). In addition, peripherally restricted MOR antagonists, such as methylnaltrexone, have proven clinically efficacious in treating opiate-induced constipation. MOR agonists, including the peripherally restricted agonist loperamide, are commonly used as antidiarrheals.A large...

show abstract

Section: This Article Provides a Detailed Characterization Of The -Opmentioning

confidence: 99%

Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

Lay

Carbone

DiCello

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…[17][18][19] DA-9701 has shown affinity for the dopamine (D) 2 , 5-hydroxytryptamine (5-HT) 4 , 5-HT 1A , and 5-HT 1B receptors. 13,11,15 It has antagonistic effects on the D 2 receptors and agonistic effects on the 5-HT 4 , 5-HT 1A and 5-HT 1B receptors. 14,15,20 It has been reported that DA-9701 can improve delayed gastric emptying and may be effective as a prokinetic agent.…”

mentioning

confidence: 99%

The Effect of DA-9701 in Opioid-induced Bowel Dysfunction of Guinea Pig

Hussain

Rhee

Lee

et al. 2016

J Neurogastroenterol Motil

View full text Add to dashboard Cite

Background/AimsOpioid induced bowel dysfunction (OIBD) is associated with decreased gastrointestinal (GI) propulsive activity due to intake of opioid analgesics. DA-9701, a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber has promising effects on GI motor function. Therefore, we aim to evaluate the prokinetic effects of DA-9701 in an OIBD model of guinea pig. MethodsThe ileal and distal colon muscle contraction in presence of different doses of DA-9701, morphine, and combination (morphine + DA-9701) was measured by tissue bath study. The prokinetic effect of DA-9701 was assessed by charcoal transit and fecal pellet output assay in an OIBD model of guinea pig.Results DA-9701 significantly increased the amplitude and area under the curve of ileal muscle contraction, while there was insignificant effect on the distal colon compared to the control. The maximal amplitude of ileal muscle contraction was acquired at a concentration of 10 μg/mL of DA-9701. In contrast, morphine significantly decreased the amplitude of ileal and distal colon muscle contraction compared to the control. Morphine delayed both upper (P < 0.01) and lower (P < 0.05) GI transit, and delayed GI transit was restored by the administration of DA-9701. Morphine induced reduction of contractility was significantly ameliorated by addition of DA-9701 in both ileal and distal colon muscles. ConclusionsDA-9701 significantly increased the amplitude of contraction of the ileal muscle, however the distal colon muscle contraction was insignificant. Additionally, it restored delayed upper and lower GI transit in an OIBD model of guinea pig, and it might prove to be a useful candidate drug in a clinical trial for OIBD. (J Neurogastroenterol Motil 2016;22:529-538)

show abstract

“…Drugs we have worked on in this category include cisapride (Propulsid Ò ), tegaserod (Zelnorm Ò ), alosetron (Lotronex Ò ), and lubiprostone (Amitiza Ò ) [46][47][48].…”

Section: Pharmaceutical Industrymentioning

confidence: 99%