Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats.
Scratching is the behavioral manifestation of pruritus. The pruritus of cholestasis can be severe, intractable and affect the quality of life. We investigated if ethynylestradiol (EE)-induced cholestasis is associated with scratching in rats and if nalfurafine, a kappa opioid receptor agonist with antipruritic effects in human uremic pruritus, would antagonize such scratching. Chronic injection of EE (2 mg/kg, s.c., for 14 days) induced cholestasis as documented by increased serum concentrations of bile acids and caused a higher incidence of body scratching compared to vehicle, thus providing an animal model to study scratching behavior secondary to cholestasis. Pretreating the rats with nalfurafine (0.005-0.04 mg/kg, s.c.) inhibited EE-induced scratching dose-dependently with an A(50) value of 0.013 (0.009-0.021) mg/kg. Serum levels of dynorphin A and nitric oxide were decreased in rats with cholestasis compared to control animals. Our data suggest that (a) nalfurafine has the potential to relieve cholestatic pruritus and (b) both kappa opioid and nitric oxide systems are involved, at least in part, in mediating the pruritus of cholestasis.
Inan
Saadet
S
Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA. sinan@temple.edu
Cowan
Alan
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002779:Cholestasis / Q000139:chemically induced / Q000150:complications*; D004997:Ethinyl Estradiol / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D008297:Male; D009019:Morphinans / Q000494:pharmacology* / Q000627:therapeutic use; D011537:Pruritus / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use
D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D004997:Ethinyl Estradiol