New insights into the role of endogenous opioids in the pathogenesis of gastrointestinal and liver disease
- 1Centre for Hepatology, Department of Medicine, UCL Medical School, University College London, London, UK
- 2Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Dr Kevin Moore, Centre for Hepatology, Royal Free Campus, UCL Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK;
- Revised 15 December 2008
- Accepted 3 February 2009
Opiates have been known for centuries for their role in the management of pain. In 1975, Hughes and Kosterlitz isolated two endogenous peptides (enkephalins) from pig brain with high affinity for opioid receptors.1 Later, other groups of endogenous opioids, the endorphins, dynorphins and endomorphins were discovered. These endogenous opioid peptides bind to multiple opioid receptors (mu, delta and kappa) which belong to the G protein-coupled super-family of receptors. Initially the function of these peptides was thought to be limited to analgesia and the modulation of gastrointestinal motility; however, recent data have elucidated that endogenous opioids can regulate cell growth, differentiation and survival in non-neuronal systems such as inflammatory cells and biliary epithelia, as well as hepatic stellate cells.2–5
The involvement of endogenous opioids in the pathophysiology of gastrointestinal and hepatobiliary disease has been widely studied in recent years. The most significant observations directing the interest toward this field have been: (1) endogenous opioids exhibit anti-inflammatory properties in the gut and this effect may have implication in the management of inflammatory bowel disease;6 (2) biliary injury is associated with increased production of endogenous opioids7 and opioid receptor antagonists have a beneficial effect on pruritus of cholestasis;8 (3) endogenous opioids modulate hepatic stellate cell activation and opioid receptor antagonists show an anti-fibrotic effect in experimental models of hepatic fibrosis;4 5 (4) a novel opioid receptor (opioid growth factor receptor) has recently been identified which plays an important role in the negative regulation of cell proliferation in pancreatic cancer.9
The purpose of this brief review is to examine the available data concerning the role of endogenous opioids in the pathophysiology of gastrointestinal and liver disease and to discuss new therapeutic possibilities of opioid manipulation in gastrointestinal diseases.
Endogenous opioids and inflammatory bowel disease
Inflammatory bowel disease (IBD) is a chronic, relapsing condition involving complex interactions between genes and the environment. The mechanisms triggering the initial attack and relapses are not well understood. In the past several years the involvement of neuropeptides (eg, endogenous opioids) has been implicated in the pathophysiology of IBD.10 The demonstration of opioid peptide and mu opioid receptor expression by cells involved in the inflammatory response2 has led to new investigations showing the roles of mu opioid receptor modulators in the regulation of the immune system and inflammatory reactions in different tissues including the gut.
In a pioneering study, Philippe et al, provided evidence that the mu opioid receptor plays a role in the control of gut inflammation.6 They showed that mu opioid receptor knockout mice were highly susceptible to colon inflammation, with a significant increase in mortality rate after induction of chemical colitis. Furthermore, treatment of wild-type mice with selective peripheral mu opioid receptor agonists was associated with a naloxone-sensitive reduction in gut inflammation in experimental models of colitis.6 The mechanistic basis of these observations suggested that the anti-inflammatory effects of the mu opioid receptor in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunological events required for the development of colon inflammation in mice and patients with IBD.6 In a complementary human study, Philippe et al investigated the expression of the mu opioid receptor in healthy and inflamed small bowel and colonic tissues, as well as peripheral blood mononuclear cells purified from healthy donors and patients with IBD.11 This study demonstrated the upregulation of mu opioid receptors in inflamed tissue from patients with Crohn’s disease and ulcerative colitis, and localised the upregulation, at least in part, to lamina propria mononuclear cells, including CD4+ and CD8+ T lymphocytes.11 This report also showed that a selective mu receptor agonist reduced the secretion of the pro-inflammatory cytokine, tumour necrosis factor α (TNFα), from colonic tissue from IBD and control subjects.11 Whether these observations are clinically relevant or not needs further investigation. However these data suggest caution should be used when using opioid receptor antagonists (eg, naloxone and naltrexone) in patients with IBD.
Apart from the role of mu opioid receptors in the modulation of immune system and inflammation, recent observations have shown that kappa opioid agonists exhibit powerful anti-inflammatory action.12 It appears that this kappa-opioid related anti-inflammatory action is exerted via (1) reduced adhesion molecule expression; (2) inhibition of cell trafficking; (3) reduced TNFα release and expression, and (4) alterations in mRNA expression of other neuropeptides such as substance P and calcitonin-gene related polypeptides.12 Although the involvement of kappa opioid receptors during the course of IBD has not been studied extensively, kappa agonists (such as niravoline) are being studied for their aquaretic role in the management of ascites and hyponatraemia in cirrhosis.13 An additional anti-inflammatory action might be beneficial in the management of complications of cirrhosis associated with systemic inflammation (eg, hepatic encephalopathy or gastrointestinal bleeding).
Endogenous opioids and biliary injury
Studies from the 1980s in patients with primary biliary cirrhosis represent the earliest evidence of a correlation between the plasma levels of endogenous opioids and liver disease.14 This concept led to the observation that opioid receptor antagonists ameliorate pruritus in patients with cholestasis.8 14 Although opioid antagonist therapy has since been used therapeutically for the treatment of pruritus in cholestatic liver disease, the physiological basis of its actions has not completely been understood.
Neuropeptides and neurendocrine hormones play a significant role in the regulation of cholangiocyte function and proliferation.15 In addition, in the course of cholangiopathies, the biliary epithelium acquires neurendocrine features that are not present in the normal liver.15 16 In a series of studies by Alpini’s group, it has been demonstrated that such a neuroendocrine trans-differentiation allows cholangiocytes to synthesise and secrete the neuroendocrine hormones (such as serotonin and opioid peptides), which then acts in an autocrine–paracrine fashion to limit the growth of these cells.3 15 17
In the case of endogenous opioids, it has been demonstrated that bile duct epithelium express pre-pro-enkephalin mRNA following injury, which encodes enkephalin peptides.7 Apart from the synthesis of opioid peptides, these cells also express opioid receptors, which suggest the existence of an autocrine loop of opioid peptides which controls the function and the growth of cholangiocytes following cholangiocyte injury.17 In a landmark study, Marzioni et al, investigated the function of different subtypes of opioid receptors in cholangiocytes and found that these cells express two functionally active receptors, the mu and the delta opioid receptors.3 Interestingly they also observed that mu receptor activation results in a very slight increase of cell proliferation, whereas delta receptor activation determined a marked reduction of the cholangiocyte proliferative response to experimental cholestasis. Further in vitro and in vivo studies by the same group of investigators showed that in comparison with mu receptor, delta opioid receptor is functionally activated mostly by the endogenous opioid peptides in the course of cholestasis.3
These new data are important since they demonstrate that endogenous opioids are part of an active autocrine loop that modulates cholangiocytes proliferation following biliary injury (fig 1). These data also suggest that endogenous opioids lead to the pruritus of cholestasis secondary to their role as regulators of biliary injury and repair,17 and that blockade may have a deleterious or beneficial effect in the long term. To determine whether this autocrine loop is clinically relevant, long-term epidemiological studies are needed to investigate the effects of chronic opioid blockade in patients with cholestatic liver disease.
Endogenous opioids and hepatic stellate cells
Most of the reported effects of opioids on the liver are mediated by modulation of the central nervous regulation of hepatic function.14 For instance, Roberts et al showed that activation of opioid receptors can decrease hepatic glutathione levels via a central nervous system mechanism.18 Recent reports have shown that the liver itself may also be a direct site of action of opioids. Despite the fact that the expression of mu and delta opioid receptors has been reported in rat liver,19 the distribution of these receptors in different hepatic cells is not very well understood. There are no data to demonstrate expression of opioid receptors on hepatocytes, and the modulation of hepatocyte apoptosis by opioids is probably mediated by the kupffer cells which are known to express opioid receptors.20
The expression of both mu and delta opioid receptors has also been shown in activated hepatic stellate cells;4 5 This is particularly important as modulation of hepatic stellate cells activity by endogenous opioids can potentially make opioid receptors a promising target for anti-fibrotic therapies in cirrhosis (fig 1). We were the first group to demonstrate that in vivo inhibition of the opioid system in a rat model of chronic cholestasis significantly prevented the development of hepatic fibrosis, and this was subsequently confirmed by others in dimethylnitrosamine-induced liver injury.4 5
In vitro studies indicate that the expression of both delta and mu opioid receptors in activated hepatic stellate cells may contribute to the maintenance of activated phenotype in the stellate cell-derived myofibroblast-like cells.4 5 Thus, activation of delta opioid receptors is shown to increase the expression of the genes encoding pro-collagen I and inhibits apoptosis of activated myofibroblasts.4 De Minicis et al has also demonstrated that stimulation of opioid receptors mediates hepatic stellate cell proliferation and collagen synthesis via activation of the calcium-dependent protein kinase C/phosphatidylinositol 3-kinase (IP3/CamKII/PKC) signalling pathway.5
Collectively, the evidence suggests that the biliary epithelium acquires neurendocrine features in response to liver injury. This leads to the secretion of opioid peptides by cholangiocytes, which act on both activated hepatic stellate cells to induce fibrogenesis, and on biliary epithelium to suppress proliferation (fig 1). It has been suggested that during chronic liver injury, hepatic stellate cell-derived myofibroblasts express opioid receptors rendering them susceptible to opioid peptides produced by epithelial compartments (eg, cholangiocytes) in the liver, which can then contribute to maintenance of the activated phenotype in these cells.4 16
The concept of modulation of hepatic stellate cells might have implications in the pathogenesis of hepatic fibrosis in intravenous drug abusers, many of whom are positive for hepatitis C virus (HCV). The injection of opiates may contribute to maintenance of the activated phenotype in hepatic stellate cells leading to favourable conditions for the progression of collagen accumulation and a possible acceleration of HCV-induced hepatic fibrosis.21 In addition, it has also been shown that morphine enhances the progression of hepatitis C by interacting with the viral replication process.22 To determine whether this type of interaction is clinically relevant, long-term epidemiological studies are needed. These may lead to important changes in our therapeutic approach to the treatment of hepatitis C in intravenous drug abusers.
Endogenous opioids and pancreatic cancer
Zagon and colleagues have extensively studied the role of endogenous opioid peptides in regulation cell proliferation in tumor cells.9 These investigations led to the discovery of a novel opioid receptor which negatively regulates cell proliferation in a variety of cells including human pancreatic adenocarcinoma.23 This receptor binds to the native opioid peptide, met-enkephalin, and in view of its action is termed “opioid growth factor receptor”. This receptor is located in the outer nuclear envelope and contributes to the maintenance of the equilibrium in cell replication by targeting cyclin-dependent inhibitory kinase pathways.9 Opioid growth factor receptor exhibits no structural resemblance to that of classical opioid receptors and is not pharmacologically blocked by selective mu, delta or kappa receptor antagonists.9
The discovery of an opioid growth factor receptor in human pancreatic cancer is important, since it may lead to novel anti-neoplastic therapies which target ligands such as met-enkephalin. Cell culture and experimental studies support a potent anti-proliferative role for opioid growth factor receptor ligands in experimental models of pancreatic cancers.24–26 However, human studies undertaken so far are preliminary but show that met-enkephalin can be safely administered to patients with advanced pancreatic cancer.27 Further studies are needed to determine the efficacy of opioid growth factor alone or in combination with present treatments of pancreatic cancer.
Endogenous opioids exhibit a wide range of biological functions in the gastrointestinal and hepatobiliary system. Beside their role in regulation of parenchymal cell function and proliferation, opioids are potent modulators of innate and acquired immune system.28 This is important given that autoimmune mechanisms are extensively involved in a variety of pathologies observed in the gut and the hepatobiliary system. However, our knowledge of the contribution of opioids in immune-related mechanisms in hepatobiliary system is still limited and needs further investigation.
In addition, many pathological process discussed in this review (eg, liver fibrosis) share common mechanisms in different compartments of gastrointestinal and hepatobiliary system. A well-known example is the mechanism of hepatic fibrosis which exhibits a high degree of similarity with fibrosis observed in the pancreas of patients with chronic pancreatitis or other chronic inflammatory conditions in the gastrointestinal tract.29 The modulation of hepatic fibrosis by endogenous opioid has been investigated in different models in recent years. These studies can lead us to investigate the role of opioid peptides in scar formation and fibrogenesis in other organs within the gastrointestinal tract.