Project 3: Central Processing of Cholestatic Pruritus
Project Managers:
Prof. Dr. C. Forster
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Prof. Dr. H. Handwerker
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About:
The key objective of this project is to identify the organization of the central nervous network activated by itch sensations due to endogenous pruritogens in patients suffering from chronic itch linked to internal diseases compared with healthy subjects and patients suffering from similar diseases but without chronic itch.
Pruritus is a common symptom in various hepatobiliary disorders such as primary biliary cholangitis and primary sclerosing cholangitis. The identification of one potential pruritogen has recently been successful by screening sera of patients suffering from cholestatic pruritus for neuronal activation. This assay unravelled lysophosphatidic acid as a potent neuronal activator. Lysophosphatidic acid (LPA) and the activity of the LPA-forming enzyme autotaxin (ATX) were found strongly increased in sera of cholestatic patients and correlated well to the intensity of itch. LPA injected into mouse skin (neck) induced scratching responses.
Experimental stimulation paradigms have been successfully established for central imaging of itch processing in volunteers and patients. However, these studies were designed to study acute pruritus in healthy skin and were based on the typical on-off-design. In contrast, pruritus in patients is usually chronic and therefore requires new approaches to investigate presumed central changes of itch processing, leading to these questions:
Pruritus is a common symptom in various hepatobiliary disorders such as primary biliary cholangitis and primary sclerosing cholangitis. The identification of one potential pruritogen has recently been successful by screening sera of patients suffering from cholestatic pruritus for neuronal activation. This assay unravelled lysophosphatidic acid as a potent neuronal activator. Lysophosphatidic acid (LPA) and the activity of the LPA-forming enzyme autotaxin (ATX) were found strongly increased in sera of cholestatic patients and correlated well to the intensity of itch. LPA injected into mouse skin (neck) induced scratching responses.
Experimental stimulation paradigms have been successfully established for central imaging of itch processing in volunteers and patients. However, these studies were designed to study acute pruritus in healthy skin and were based on the typical on-off-design. In contrast, pruritus in patients is usually chronic and therefore requires new approaches to investigate presumed central changes of itch processing, leading to these questions:
- Does intradermally injected LPA provoke different itch sensations between volunteers and patients with cholestatic itch?
- Do central activation patterns differ between LPA, histamine or cowhage-induced itch in volunteers?
- Do central activation patterns and their connectomes in patients with cholestatic itch differ between LPA, typical pruritogens and localized stimulation with algogens (using capsaicin spicules) and do they differ between patients suffering from non-itching cholestatic diseases and healthy volunteers?
- Which alterations are present in cutaneous nerve fibres and expression patterns in skin of patients with hepatobiliary disorders suffering from chronic pruritus?
Related Publications:
- Forster C, Handwerker HO: Central Nervous Processing of Itch and Pain. In: Itch: Mechanisms and Treatment (Akiyama T, Carstens E, eds.). Boca Raton, FL: CRC Press, 2013; 409-419
- Hartmann EM, Handwerker HO, Forster C: Gender differences in itch and pain related sensations provoked by histamine, cowhage and capsaicin. Acta Derm Venereol.; 2015, 95: 25–30
- Hegade VS, Krawczyk M, Kremer AE, Kuczka J, Gaouar F, Kuiper EM, van Buuren HR, Lammert F, Corpechot C, Jones DE. The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther. 2016;43(2):294-302.
- Herde L, Forster C, Strupf M, Handwerker HO: Itch induced by a novel method leads to limbic deactivations a functional MRI study. J Neurophysiol, 2007, 98:2347–2356
- Kosteletzky F, Namer B, Forster C, Handwerker HO: Impact of Scratching on Itch and Sympathetic Reflexes Induced by Cowhage (Mucuna pruriens) and Histamine. Acta Derm Venereol, 2009, 89: 271–277
- Kremer AE, Martens JJ, Kulik W, Ruëff F, Kuiper EM, Buuren HR, van Erpecum KJ, Kondrackiene J, Prieto J, Rust C, Geenes VL, Williamson C, Moolenaar WH, Beuers U, Oude Elferink RP. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010;139(3):1008-18.
- Kremer AE, Dijk RV, Leckie P, Schaap FG, Kuiper EM, Mettang T, Reiners KS, Raap U, Buuren HR, Erpecum KJ, Davies NA, Rust C, Engert A, Jalan R, Elferink RP, Beuers U. Autotaxin is elevated in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions. Hepatology 2012;56(4):1391-400.
- Kremer AE, Feramisco J, Reeh PW, Beuers U, Oude Elferink RP. Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta. 2014;1842(7):869-92.
- Kremer AE, Bolier R, Dixon PH, Geenes V, Chambers J, Tolenaars D, Ris-Stalpers C, Kaess BM, Rust C, van der Post JA, Williamson C, Beuers U, Oude Elferink RP. Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. J Hepatol. 2015;62(4):897-904.
- Vierow V, Forster C, Vogelgsang R, Dörfler A, Handwerker HO: Cerebral networks linked to itch-related sensations induced by histamine and capsaicin. Acta Derm Venereol.; 2015, 95: 645–652