New insights into the role of endogenous opioids in the pathogenesis of gastrointestinal and liver disease

Mani, Ali R.; Moore, Kevin

doi:10.1136/gut.2007.141648

Cited by 13 publications

(9 citation statements)

References 31 publications

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“…We also showed that naltrexone markedly attenuated the development of hepatic fibrosis as well as matrix metalloproteinase 2 activity in bile‐duct ligated rats. Moreover, we reported that the development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S‐nitrosothiols, which were partially or completely normalized by treatment with naltrexone respectively . Therefore, either direct action on cardiovascular tissue or protection against liver damage may be responsible for recovery of cardiovascular parameters after naltrexone administration in bile‐duct ligated rats.…”

Section: Hypotension and Impaired Vascular Reactivity In Cholestasismentioning

confidence: 97%

Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms

Moezi

Dehpour

2012

Liver International

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Cholestatic liver disease is associated with widespread derangements in the cardiovascular system, such as bradycardia, hypotension, QT prolongation and peripheral vasodilation; it is also associated with increased susceptibility to postoperative renal failure and haemorrhagic shock. A number of cellular signalling pathways have been shown to contribute to these abnormalities. In this article, we briefly review recent in vivo and in vitro findings in the field in an attempt to highlight the areas of agreement and areas of controversy. In this review, we will summarize pathogenic mechanisms underlying cardiac and vascular abnormalities in obstructive cholestasis. It seems that cardiovascular dysfunction is likely because of bile acids as one of the predominant factors. Other important factors which might play roles in these abnormalities are increased nitric oxide, endogenous opioids and endocannabinoids. These three factors interact with each other to exert vasodilation and impaired cardiovascular responses to sympathetic stimulation.For many years, surgeons were puzzled and distressed by the frequent complications of hypotension and kidney failure after surgery on patients with obstructive jaundice (1-3). Increased recognition and awareness of this clinical problem have led to extensive clinical and laboratory investigations, resulting in a better appreciation of the relationship between the liver, the kidney and the cardiovascular system. The first to make a systematic study of the bradycardia of jaundice was RÖ hrig, in 1863, who showed that the bile salts are responsible for the bradycardia and low blood pressure of jaundice (4). In 1911, Clairmont and von Haberer first described the occurrence of renal failure developing after surgery for obstructive jaundice. Following these original observations, numerous clinical series have been reported in the literature, all of which point to a strong association between post-surgical renal failure and obstructive jaundice. A review of the different series indicates that the overall mortality rate for patients undergoing surgery for obstructive jaundice is 16% to 18%. Acute renal failure occurs in approximately 8% to 10% of patients requiring surgery for relief of obstructive jaundice and contributes to eventual mortality in 70% to 80% of those who develop it (5).In this review, we attempt to summarize the pathogenic mechanisms underlying cardiac and vascular abnormalities in cholestasis. Human data in this field is relatively scarce; majority of the findings discussed in this article are based on animal studies. The Figure 1 summarizes the major pathologic mechanisms in the blood vessels and/or the heart. Cardiac abnormalities in cholestasisThe association of obstructive jaundice with bradycardia has been known for over a century (5). It is also well known that cholestatic liver disease is associated with hypotension (6, 7), QT prolongation (8) and hyporesponsiveness of the heart to adrenergic stimulation (9, 10). Literature reports also have described a card...

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Section: Hypotension and Impaired Vascular Reactivity In Cholestasismentioning

confidence: 97%

Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms

Moezi

Dehpour

2012

Liver International

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“…11 Opioids are a class of neuropeptides that have traditionally been used as analgesics; however, emerging literature associates this class of neuropep-tide with intestinal proliferation and inflammation. 12 Vertebrates traditionally express three types of opioid receptors: mu, delta, and kappa, all of which are Gprotein-coupled receptors that preferentially bind to G i proteins. Binding of ligand to these receptors leads to the prototypical inactivation of neural pain fibers.…”

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confidence: 99%

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Goldsmith

Uronis

Jobin

2011

The American Journal of Pathology

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Opiates have long been used as analgesics to relieve pain associated with various medical conditions. Here, we evaluated the effect and mechanism of mu opioid signaling on the intestinal wound healing response and assessed downstream pathways known to be protective against intestinal injury. Mice (C57BL/6) were exposed to 3% dextran sodium sulfate (DSS) for 7 days or 4% DSS for 5 days followed by 7 days of water. The mu opioid receptor (MOR)-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA) and the antagonist cyprodime were injected s.c. daily for in vivo studies or used for in vitro analysis. We found that MOR activation attenuated DSS-induced histologic and gross intestinal injury and weight loss; diminished Ifng, Tnf, and Il6 mRNA expression; and promoted intestinal healing during recovery. DALDA also enhanced colonocyte proliferation (Ki-67 staining) by 350%. MOR activation increased Stat3 phosphorylation in both DALDA-treated mice and the CMT-93 cell line. Importantly, DALDAinduced colonocyte migration was completely ablated by shStat3 knockdown. Together, this work shows that MOR activation protects against and enhances recovery from DSS-induced intestinal injury. This is associated with an increase in Stat3 activation. Furthermore, Stat3 is required for DALDA-induced colonocyte migration. Consequently, manipulation of MOR signaling may represent a novel means to promote mucosal healing and to maintain intestinal homeostasis after intestinal injury.

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“…Endogenous opioids are thought to play a role in the physiological regulation of gut function 154–156. Studies with opioid receptor antagonists support this idea.…”

Section: Recent Advances In the Use Of Opioids For Cancer Pain: Opioimentioning

confidence: 99%

Recent advances in the use of opioids for cancer pain

Droney

Riley²

2009

JPR

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Opioids are the mainstay of treatment for moderate to severe cancer pain. In recent years there have been many advances in the use of opioids for cancer pain. Availability and consumption of opioids have increased and opioids other than morphine (including methadone, fentanyl, oxycodone) have become more widely used. Inter-individual variation in response to opioids has been identified as a significant challenge in the management of cancer pain. Many studies have been published demonstrating the benefits of opioid switching as a clinical maneuver to improve tolerability. Constipation has been recognized as a significant burden in cancer patients on opioids. Peripherally restricted opioid antagonists have been developed for the prevention and management of opioid induced constipation. The phenomenon of breakthrough pain has been characterized and novel modes of opioid administration (transmucosal, intranasal, sublingual) have been explored to facilitate improved management of breakthrough cancer pain. Advances have also been made in the realm of molecular biology. Pharmacogenetic studies have explored associations between clinical response to opioids and genetic variation at a DNA level. To date these studies have been small but future research may facilitate prospective prediction of response to individual drugs.

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New insights into the role of endogenous opioids in the pathogenesis of gastrointestinal and liver disease

Cited by 13 publications

References 31 publications

Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms

Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Recent advances in the use of opioids for cancer pain

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