Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin

Varadi, D. P.

doi:10.1001/archderm.109.5.678

Cited by 41 publications

(35 citation statements)

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“…The findings that BA levels are elevated in serum and skin of cholestatic patients (18,19), that BAs cause itch (20,21), and that BA-binding resins are an effective treatment (22) implicate BAs as causative agents of cholestatic itch. We observed hyperexcitability of DRG neurons and release of transmitters of itch and analgesia at BA concentrations, in line with the elevated levels of total BAs detected in serum of patients with cholestatic disease (61).…”

Section: Discussionmentioning

confidence: 99%

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The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

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Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucineenkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide-and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

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Section: Discussionmentioning

confidence: 99%

“…Bile acids (BAs) are potential mediators, since cholestatic patients have increased BA concentrations in the circulation (18) and skin (19), and application of BAs to the skin causes itch (20,21), whereas bile salt-binding resins relieve cholestatic pruritus (22). Alterations in opioids and their receptors may also contribute.…”

Section: Introductionmentioning

confidence: 99%

The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

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“…17,23,27) In healthy humans, naloxone increases itch thresholds to histamine. 18) In contrast, µ-opioid receptor agonists elicit facial scratching following intracisternal injection and body scratch- ; the failure of histamine to elicit scratching in mice (1974) 8) ; scratching induced by intracerebroventricular and intrathecal injections of bombesin in rats (1983); responses of primary afferents to cowhage stimulation in cats (1987) 10,11) ; scratching induced by injections of opioids into the medullary dorsal horn in monkeys (1992,1993); and scratching induced by injection of morphine into the medullary dorsal horn in rats (1995). [28][29][30] However, opioid antagonists may act on the lower brainstem rather than on the spinal dorsal horn and the periphery to inhibit itch signaling.…”

Section: Scratching Behaviors and Opioid Receptorsmentioning

confidence: 99%

“…7) An intradermal injection of histamine was also reported not to elicit scratching in mice in 1974. 8) To compound the issue further, a 1987 study claimed that the "scratching" behavior observed in arthritic rats was due to underlying chronic pain. 9) Electrophysiological studies showed that cutaneous stimulation with cowhage spicules, which elicit itching in humans, 5) activated C-polymodal nociceptors and myelinated mechanoreceptors in cats.…”

Section: Introductionmentioning

confidence: 99%

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

Kuraishi

2015

Biological & Pharmaceutical Bulletin

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Itch is a sensation that provokes a desire to scratch. Mast-cell histamine was thought to be a key itch mediator. However, histamine and mast-cell degranulation were reported not to elicit scratching in animals. It was difficult to investigate the pathophysiology of itching and to evaluate the antipruritic efficacy of chemical agents in the early 1990 s. We showed that hind-paw scratching and biting were elicited by stimulation with pruritogenic agents in mice. Those results demonstrated for the first time that cutaneous itching could be evaluated behaviorally in animals. We established various animal models of pathological itch of the skin (dry skin, mosquito allergy, surfactant-induced pruritus, and herpes zoster) and mucus membranes (pollen allergy). Mast-cell histamine did not play a key role in itching in any animal model examined except for the pollen allergy model. Histamine is not an exclusive itch mediator of mast cells; tryptase and leukotriene B 4 released from mast cells also act as itch mediators. Epidermal keratinocytes release several itch mediators, such as leukotriene B 4 , sphingosylphosphorylcholine, thromboxane A 2 , nociceptin, nitric oxide, and histamine, which may play important roles in pathological itching. Appropriate animal models of pathological itching are needed for pharmacological evaluation of the antipruritic efficacy of chemical agents.

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“…2,3 Furthermore, pruritus can be produced by the intradermal instillation of bile acid. 4 Although the exact pathogenesis of pruritus associated with cholestasis continues to be debated, given the debilitating nature of the symptom, treatment is necessary in many patients. We report the successful use of serotonin or the 5-hydroxytryptamine type 3 (5-HT 3 ) antagonist ondansetron to treat pruritus associated with cholestasis following the prolonged intensive care unit (ICU) course of a 16-year-old.…”

Section: Introductionmentioning

confidence: 99%

Ondansetron to Treat Pruritus Due to Cholestatic Jaundice

Dillon

Tobias

2013

The Journal of Pediatric Pharmacology and Therapeutics

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Intractable itching is a symptom of cholestatic liver disease of various causes that is bothersome and difficult to manage. Although treatment of the primary cause of cholestasis is paramount in resolving the issue, given the debilitating consequences of pruritus, symptomatic treatment is frequently necessary. Although many medications including cholestyramine, rifampin, opioid antagonists (i.e., naloxone, naltrexone), phenobarbital, and antihistamines have been used to treat cholestatic-induced pruritus, none has resulted in uniform success. We report anecdotal success with the use of ondansetron to treat pruritus associated with cholestasis following prolonged intensive care unit course of a 16-year-old. The theories accounting for pruritus with cholestasis are presented, treatment options are reviewed, and the role of ondansetron in the treatment of pruritus is discussed. INDEx TERMS

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Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin

Cited by 41 publications

References 0 publications

The TGR5 receptor mediates bile acid–induced itch and analgesia

The TGR5 receptor mediates bile acid–induced itch and analgesia

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

Ondansetron to Treat Pruritus Due to Cholestatic Jaundice

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