Elsevier

Medical Hypotheses

Volume 110, January 2018, Pages 86-89
Medical Hypotheses

The pruritus of cholestasis: From bile acids to opiate agonists: Relevant after all these years

https://doi.org/10.1016/j.mehy.2017.11.002Get rights and content

Abstract

The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists. Obeticholic acid, an agonist of the farnesoid receptor, has been approved for the treatment of primary biliary cholangitis, a disease characterized by cholestasis; this drug is associated with pruritus, the cause of which is unknown. In animal models, bile acids, which accumulate in the body as a result of cholestasis, have been reported to cause scratching behavior mediated by the TGR5 receptor, in an opioid-dependent manner, in laboratory animals. As obeticholic acid also binds to TGR5, the pruritus caused by this drug is likely to be mediated by the opioid system. Lisophosphatidic acid, which has been reported to be increased in patients with cholestasis and pruritus, has been described to cause scratching behavior that is prevented by an opiate antagonist in laboratory animals, suggesting an opioid-receptor mediated mechanism of scratching. In summary, evidence continues to support a role of the endogenous opioid system in the pathogenesis of the pruritus of cholestasis

Introduction

In 1990, we postulated that “a major factor contributing to the pruritus of cholestasis is increased availability of opiate agonist ligands at opioid receptors in the brain” [1] i.e. increased opioidergic neurotransmission or tone. A series of clinical and basic studies have provided evidence in support of this hypothesis, and in support of the use of opiate antagonists for the treatment of the pruritus of cholestasis [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The basis for this hypothesis was the reported opiate withdrawal-like syndrome precipitated by an opiate antagonist in association with the amelioration of the pruritus in patients with cholestasis secondary to primary biliary cirrhosis [2], a name that has been recently changed to primary biliary cholangitis (PBC) [12].

In this manuscript, the author provides an interpretation of data that have evolved over the past few years, and expands the hypothesis stating that the endogenous opioid system contributes to the pruritus of cholestasis.

Section snippets

Pruritus and the endogenous opioid system

There is strong evidence to support a role of the endogenous opioid system in the mediation of pruritus of central origin: (i) the administration of morphine intrathecally to human beings is associated with pruritus, which is ameliorated and which can be prevented by opiate antagonists [13], [14], (ii) in laboratory animals, the central administration of morphine and other agonists at the mu opioid receptor is associated with scratching behavior, which is decreased and also prevented by opiate

Lisophosphatidic acid and scratching behavior

Lisophosphatidic acid (LPA), and autotaxin, the enzyme that generates its production have received some attention in the past few years as potential mediators of the pruritus of cholestasis [30], [31]. Injections of LPA in the skin of C57BL/6J female mice were reported to cause scratching behavior, which was interpreted as evidence for a pruritogenic role of LPA in cholestasis [30]. It was also reported that skin injections of LPA and that of LPM, a pan-LPA receptor agonist, were associated

Hypothesis: the pruritus associated with the administration of obeticholic acid is mediated by the endogenous opioid system

Obeticholic acid is a synthetic derivative of chenodeoxycholic acid that is an agonist at the farnesoid nuclear receptor (FXR), a bile acid sensor associated with a decrease in bile acid production [40], and which has choleretic properties [41]. Obeticholic acid, in addition to FXR, activates TGR5 (also known as GPBAR1) [42] (see above). The administration of obeticholic acid to patients with PBC [43] and to patients with nonalcoholic steatohepatitis [44] was associated with pruritus in a

Studies to test the hypothesis that the pruritus associated with obeticholic acid is mediated by the endogenous opioid system

The hypothesis that obeticholic acid triggers pruritus via the endogenous opioid system can be tested in a clinical study of continuous naloxone infusions in patients on obeticholic acid who experience pruritus. The intravenous use of the opiate antagonist would be preferable to the oral route (e.g. naltrexone) as intravenous infusions can be controlled, as needed.

Opioid receptor specificity in the mediation of scratching behavior

Animal models on scratching behavior have revealed that stimulation of the mu opioid receptor by agonist ligands is associated with scratching and the stimulation of the kappa opioid receptor, with the prevention of opiate-induced scratching, i.e. anti-scratching [16], [17], [46], [47]. In this context, nalfurafine, an agonist at the kappa opioid receptor, was reported to decrease the sensation of pruritus, as measured subjectively, in patients with PBC, in controlled studies [48], [49]. These

Conflict of interest

None.

References (50)

  • Y. Shimizu et al.

    Potentials of the circulating pruritogenic mediator lysophosphatidic acid in development of allergic skin inflammation in mice: role of blood cell-associated lysophospholipase D activity of autotaxin

    Am J Pathol

    (2014)
  • T. Lieu et al.

    The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice

    Gastroenterology

    (2014)
  • B.A. Neuschwander-Tetri et al.

    Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

    Lancet

    (2015)
  • S. Inan et al.

    Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats

    Pharmacol Biochem Behav

    (2006)
  • E.A. Jones et al.

    The pruritus of cholestasis: from bile acids to opiate agonists

    Hepatology

    (1990)
  • J.R. Thornton et al.

    Opioid peptides and primary biliary cirrhosis

    Br Med J

    (1988)
  • N.V. Bergasa

    The pruritus of cholestasis

    Semin Dermatol

    (1995)
  • K.L. Carson et al.

    Pilot study of the use of naltrexone to treat the severe pruritus of cholestatic liver disease

    Am J Gastroenterol

    (1996)
  • N.V. Bergasa et al.

    Open-label trial of oral nalmefene therapy for the pruritus of cholestasis

    Hepatology

    (1998)
  • F. Mansour-Ghanaei et al.

    Effect of oral naltrexone on pruritus in cholestatic patients

    World J Gastroenterol

    (2006)
  • A. Zellos et al.

    Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children

    J Pediatr Gastroenterol Nutr

    (2010)
  • J.C. Ballantyne et al.

    The incidence of pruritus after epidural morphine

    Anaesthesia

    (1989)
  • M.C. Ko et al.

    Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys

    J Pharmacol Exp Ther

    (2003)
  • M.C. Ko et al.

    The role of central mu opioid receptors in opioid-induced itch in primates

    J Pharmacol Exp Ther

    (2004)
  • N.V. Bergasa et al.

    Cholestasis in the male rat is associated with naloxone-reversible antinociception

    J Hepatol

    (1994)
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