title: Proteinase-activated receptor 1 contributed to up-regulation of enkephalin in keratinocytes of patients with obstructive jaundice.
abstract: BACKGROUND
  Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver disease. No studies have reported yet the expression of skin enkephalin in patients with cholestasis.
  
  
  METHODS
  Electrical pain threshold, postoperative morphine consumption, and skin enkephalin expression were measured in patients with jaundice (n = 18) and control patients (n = 16). Male Sprague-Dawley rats (n = 52) and human keratinocyte cell line HaCaT were used in vivo and in vitro studies, respectively. Nociceptive thresholds and plasma and skin levels of methionine-enkephalin were compared in protease-activated receptors-1-antagonized and control bile duct-ligated rats. In in vitro study, the effect on thrombin-induced enkephalin expression was examined and the role of extracellular regulated protein kinases 1/2 and p38 was investigated.
  
  
  RESULTS
  The authors found that: (1) the electrical pain threshold (mean ± SD) was 1.1 ± 0.1 mA in control patients, whereas it was significantly increased in patients with jaundice (1.7 ± 0.3 mA); 48-h postoperative morphine consumption was approximately 50% higher in the control group than that in the group with jaundice; (2) Skin keratinocytes enkephalin expression was increased in the patients with jaundice; (3) Protease-activated receptors-1 antagonist 1 μg·kg(-1)·day(-1) treatment to the bile duct-ligated rats significantly reduced plasma levels of methionine-enkephalin, nociceptive thresholds, and keratinocytes enkephalin expression; and (4) protease-activated receptors-1 activation induced enkephalin expression through phosphorylation of extracellular regulated protein kinases 1/2 and p38 in keratinocytes.
  
  
  CONCLUSIONS
  Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.
authors.affiliation: From the Department of Anesthesiology and Intensive Care Unit, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China (K.-M.T., Y.T., C.-Y.C., L.-Q.Y., Z.-J.L., Y.-M.S., W.-F.Y.); and Department of Cardiothoracic Surgery, Institute of Cardiothoracic Surgery, Changhai Hospital, the Second Military Medical University, Shanghai, China (S.-D.H.).
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Tao
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.forename: Cai-Yang
authors.initials: CY
authors.lastname: Chen
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Yang
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Lu
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Sun
authors.forename: Sheng-Dong
authors.initials: SD
authors.lastname: Huang
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yu
mesh_terms: D000328:Adult; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D002460:Cell Line; D004558:Electric Stimulation; D004744:Enkephalin, Methionine / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D041781:Jaundice, Obstructive / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D044463:Receptor, PAR-1 / Q000502:physiology*; D013917:Thrombin / Q000502:physiology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D004744:Enkephalin, Methionine; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors