Opioids. The endogenous opioid system in the skin has two components: the first component consists of peptides such as enkephalins and endorphins and the second component comprises opioid receptors (mu, kappa and delta) to which these peptides bind.23 Mu and kappa opioid receptors may act as modulators of itch in the central nervous system of animals. Mu agonists are pro-pruritogens, while kappa agonists
are antipruritic.24 selleck chemicals It has been recognized that an imbalance between these receptors may initiate itch through systemic and peripheral pathways.25 Mu receptor agonists and a peripherally restricted opioid agonist, loperamide, induced a pruritic reaction in mice. On the other hand, selective delta opioid agonists did not illicit a similar reaction.26 This pruritic response, however, was not replicated in human studies. Intradermal application of mu opioid agonists even at highest concentrations did not produce itch or mast cell degranulation.27 On the other hand, opioid levels are increased in patients with chronic liver disease and increased opioidergic neurotransmission in cholestasis is thought to mediate pruritus.28,29 Rat models demonstrated that the liver
may act as a source of endogenous opioids, namely proenkephalin-derived opioids. These opioids when present at elevated concentrations induce pruritus.30 Several studies oppose the role of opioids in cholestatic pruritus. Patients with intrahepatic cholestasis selleck of pregnancy show similar mu opioid activity as controls. Furthermore, patients with primary biliary cirrhosis having pruritus had similar opioid levels when compared to patients without pruritus.14 In patients with primary biliary cirrhosis, opioid concentrations were elevated in late
(stage 3–4) disease, which usually exhibits an improvement of symptoms such as pruritus.31 The role of opioids in cholestatic pruritus is controversial and requires further investigation. Histamine. Pregnenolone Histamine is responsible for many allergic reactions and is also thought to have a role in cholestatic pruritus. In a study by Gittlen et al. involving patients with PBC and PSC, histamine levels were elevated in patients complaining of pruritus. Histamine levels were significantly higher (P < 0.01) in pruritic (319 [132] pg/mL) (X [SD]) versus non-pruritic (227 [75] pg/mL) patients with chronic cholestatic liver disease.32 Despite the above evidence, several issues weaken the role of histamine as a mediator of pruritus. Patients with cholestatic pruritus do not exhibit dermatologic reactions seen in patients with elevated histamine levels and as discussed later in the management section, patients with cholestatic pruritus do not appear to benefit from antihistamines.