Abstract
Pruritus is a common symptom in chronic liver diseases, which may also alter thermal sensitivity. The underlying mechanisms remain unclear and treatments are not satisfactory. Portal-systemic shunting has been proposed to alter thermal sensitivity in cirrhotics. Inflammation-induced enhanced activity of the Transient Receptor Potential Vanilloid 1 (TRPV1) may contribute to pruritus and thermal hyperalgesia. Sildenafil reduces neuroinflammation in portacaval shunt (PCS) rats. The aims were to assess whether: (1) PCS rats show enhanced scratching or thermal sensitivity; (2) TRPV1 activity is enhanced in PCS rats; (3) treatment with sildenafil reduces TRPV1 activation, scratching and thermal hyperalgesia. Rats were treated with sildenafil beginning 3 weeks after surgery. The number of scratches performed were counted. Thermal hyperalgesia was analyzed using the Hargreaves’ Plantar Test. TRPV1 activation by measuring the increase in Ca2+ induced by capsaicin in dorsal root ganglia neurons. PCS rats show enhanced scratching behavior, reaching 66 ± 5 scratches/h (p < 0.01) at 21 days after surgery, while controls show 37 ± 2 scratches/h. PCS rats show thermal hyperalgesia. Paw withdrawal latency was reduced (p < 0.05) to 10 ± 1 s compared to controls (21 ± 2 s). Capsaicin-induced calcium increase was higher in dorsal root ganglia cultures from PCS rats, indicating TRPV1functional increase. PCS rats show enhanced scratching behavior and thermal sensitivity and are a good model to study these alterations in chronic liver diseases. Enhanced sensitivity and activity of TRPV1 channel underlies these alterations. Treatment with sildenafil reduces TRPV1 channel sensitivity and activity and normalizes scratching behavior and thermal sensitivity.
Similar content being viewed by others
References
Bergasa NV, Link MJ, Keogh M, Yaroslavsky G, Rosenthal RN, McGee M (2001) Pilot study of bright-light therapy reflected toward the eyes for the pruritus of chronic liver disease. Am J Gastroenterol 96(5):1563–1570
Mela M, Mancuso A, Burroughs AK (2003) Review article: pruritus in cholestatic and other liver diseases. Aliment Pharmacol Ther 17(7):857–870
Kremer AE, Oude Elferink RP, Beuers U (2011) Pathophysiology and current management of pruritus in liver disease. Clin Res Hepatol Gastroenterol 35(2):89–97
Bhalerao A, Mannu GS (2015) Management of pruritus in chronic liver disease. Dermatol Res Pract 2015:295891
Gentile S, Marmo R, Orlando C, Peduto A, Montella F, Coltorti M (1993) Alterations of vibratory and thermal peripheral sensitivity in liver cirrhosis. Ital J Gastroenterol 25(6):307–13
Seeliger S, Derian CK, Vergnolle N, Bunnett NW, Nawroth R, Schmelz M, Von Der Weid PY, Buddenkotte J, Sunderkötter C, Metze D, Andrade-Gordon P, Harms E, Vestweber D, Luger TA, Steinhoff M (2003) PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. FASEB J 13:1871–1885
Frateschi S, Camerer E, Crisante G, Rieser S, Membrez M, Charles RP, Beermann F, Stehle JC, Breiden B, Sandhoff K, Rotman S, Haftek M, Wilson A, Ryser S, Steinhoff M, Coughlin SR, Hummler E (2011) PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nat Commun 2:161
Belghiti M, Estévez-Herrera J, Giménez-Garzó C, González-Usano A, Montoliu C, Ferrer-Montiel A et al (2013) Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease. J Biol Chem 288(14):9675–9685
Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albrecht J, Blei AT (2009) Members of the ISHEN commission on experimental models of HE. Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29(6):783–788
Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 41(2):299–306
Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, Fustero S, Delgado O, Taoro-Gonzalez L et al (2015) Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation 12:195
Mixcoatl-Zecuatl T, Aguirre-Bañuelos P, Granados-Soto V (2000) Sildenafil produces antinociception and increases morphine antinociception in the formalin test. Eur J Pharmacol 400(1):81–87
Mansouri MT, Naghizadeh B, Ghorbanzadeh B (2014) Sildenafil enhances the peripheral antinociceptive effect of ellagic acid in the rat formalin test. Indian J Pharmacol 46(4):404–408
Lee SH, Fisher B (1961) Portacaval shunt in the rat. Surgery 50:668–672
Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88
Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139(7):1353–1365. doi:10.1016/j.cell.2009.11.034.
Ng K, Lin CS, Murray NM, Burroughs AK, Bostock H (2007) Conduction and excitability properties of peripheral nerves in end-stage liver disease. Muscle Nerve 35(6):730–738
Planells-Cases R, Garcìa-Sanz N, Morenilla-Palao C, Ferrer-Montiel A (2005) Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflugers Arch 451(1):151–159
Monfort P, Corbalán R, Martinez L, Lopez-Talavera J, Córdoba J, Felipo V (2001) Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis. Neuroscience 104:1119–1125
Rodrigo R, Erceg S, Rodriguez-Diaz J, Saez-Valero J, Piedrafita B, Suarez I, Felipo V (2007) Glutamate-induced activation of nitric oxide synthase is impaired in cerebral cortex in vivo in rats with chronic liver failure. J Neurochem 102(1):51–64
Monfort P, Erceg S, Piedrafita B, Llansola M, Felipo V (2007) Chronic liver failure in rats impairs glutamatergic synaptic transmission and long-term potentiation in hippocampus and learning ability. Eur J Neurosci 25:2103–2111
Miñana MD, Corbalán R, Montoliu C, Teng CM, Felipo V (1999) Chronic hyperammonemia in rats impairs activation of soluble guanylate cyclase in neurons and inlymphocytes: a putative peripheral marker for neurological alterations. Biochem Biophys Res Commun 257(2):405–409
Corbalán R, Montoliu C, Miñana MD, Del Olmo JA, Serra MA, Aparisi L, Rodrigo JM, Felipo V (2002) Altered modulation of soluble guanylate cyclase by nitric oxide in patients with liver disease. Metab Brain Dis 17(4):295–301
Agusti A, Cauli O, Rodrigo R, Llansola M, Hernández-Rabaza V, Felipo V (2011) p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts. Gut 60:1572–1579
Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with porto-caval shunts. Hepatology 46:514–519
Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A et al (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Behav Brain Res 250:230–237
Raposo C, Nunes AK, Luna RL, Araújo SM, da Cruz-Höfling MA, Peixoto CA (2013) Sildenafil (viagra) protective effects on neuroinflammation: the role of iNOS/NO system in an inflammatory demyelination model. Mediators Inflamm 2013:321460
Wang L, Chopp M, Szalad A, Liu Z, Bolz M, Alvarez FM, Lu M, Zhang L, Cui Y, Zhang RL, Zhang ZG (2011) Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience 193:399–410. doi:10.1016/j.neuroscience.2011.07.039
Otari KV, Upasani CD (2015) Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia. Inflammopharmacology 23(4):187–194. doi:10.1007/s10787-015-0240-5
Staurengo-Ferrari L, Mizokami SS, Silva JJ, da Silva FO, Sousa EH, da França LG, Matuoka ML, Georgetti SR, Baracat MM, Casagrande R, Pavanelli WR, Verri WA Jr. (2013) The ruthenium NO donor, [Ru(bpy)2(NO)SO3](PF6), inhibits inflammatory pain: involvement of TRPV1 and cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Pharmacol Biochem Behav 157-165. doi:10.1016/j.pbb.2013.02.006
Costa R, Marotta DM, Manjavachi MN, Fernandes ES, Lima-Garcia JF, Paszcuk AF, Quintão NL, Juliano L, Brain SD, Calixto JB (2008) Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice. Br J Pharmacol 154(5):1094–1103
Jian T, Yang N, Yang Y, Zhu C, Yuan X, Yu G, Wang C, Wang Z, Shi H, Tang M, He Q, Lan L, Wu G, Tang Z (2016) TRPV1 and PLC participate in histamine H4 receptor-induced itch. Neural Plast 2016:1682972
Gibson RA, Robertson J, Mistry H, McCallum S, Fernando D, Wyres M, Yosipovitch G (2014) A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers. PLoS One 9(7):e100610
Acknowledgments
Supported by Ministerio de Ciencia e Innovación (SAF2011-23051, CSD2008-00005; SAF2014-51851-R), Generalitat Valenciana (PROMETEO-2009-027, PROMETEOII/2014/033) and European Regional Development Funds (ERDF).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
None.
Rights and permissions
About this article
Cite this article
Belghiti, M., Agusti, A., Hernandez-Rabaza, V. et al. Sildenafil Treatment Eliminates Pruritogenesis and Thermal Hyperalgesia in Rats with Portacaval Shunts. Neurochem Res 42, 788–794 (2017). https://doi.org/10.1007/s11064-016-1980-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-016-1980-3