Proteinase-activated Receptor 1 Contributed to Up-regulation of Enkephalin in Keratinocytes of Patients with Obstructive Jaundice

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 g center dot kg(-1)center dot 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. Conclusion: Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.