Sildenafil Treatment Eliminates Pruritogenesis and Thermal Hyperalgesia in Rats with Portacaval Shunts.
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.
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Majedeline
M
Belghiti
Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain.
Ana
A
Agusti
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Vicente
V
Hernandez-Rabaza
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Andrea
A
Cabrera-Pastor
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Marta
M
Llansola
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo Yufera, 3, 46012, Valencia, Spain. vfelipo@cipf.es.
Vicente
http://orcid.org/0000-0003-3145-9538
V
Felipo
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011167:Portacaval Shunt, Surgical; D011537:Pruritus / Q000188:drug therapy* / Q000503:physiopathology; D017208:Rats, Wistar; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000627:therapeutic use; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism
D058986:Phosphodiesterase 5 Inhibitors; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D000068677:Sildenafil Citrate; D002118:Calcium
Portal-systemic shunting; Pruritus; Sildenafil; TRPV1; Thermal sensitivity