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442 SHORT COMMUNICATION Plasma Dynorphin A Concentration Reflects the Degree of Pruritus in Chronic Liver Disease: A Preliminary Report Catharina SAGITA MONIAGA 1 , Shiho IWAMOTO 1,2 , Tsuneo KITAMURA 2 , Maki FUJISHIRO 1 , Nobuaki TAKAHASHI 1 , Katsunari KINA 3 , Hideoki OGAWA 1 , Mitsutoshi TOMINAGA 1 and Kenji TAKAMORI 1 * 1 Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, 2 Department of Gastroenterology, and 3 Division of Clinical Laboratory, Juntendo University Urayasu Hospital, Chiba, Japan. *E-mail: [email protected] Pruritus is a common comorbid symptom of chronic liver disease (CLD) and can reduce the quality of life. The pathogenesis of pruritus itself remains unclear, but includes the involvement of endogenous opioids (1). Previous studies have identified 3 major types of opioid receptors, μ-type (MOR, a receptor for β-endorphins), κ-type (KOR, a receptor for dynorphins), and δ-type (a receptor for enkephalins) (2). Activation of μ-opioid re- ceptors is thought to induce pruritus, whereas activation of κ-opioid receptors is believed to have a suppressive effect (1, 3). We previously reported that the κ-opioid system was downregulated in the epidermis of patients with atopic dermatitis (AD) and that psoralen-ultraviolet A (PUVA) therapy downregulated the μ-opioid system and restored the κ-opioid system, concomitant with a decrease in visual analogue scale (VAS) score (4). Cholestasis in- creased plasma opioid levels in, both mice and humans (5, 6). In addition, the opioid antagonists, e.g. naloxone and naltrexone, have been extensively evaluated as the clinical treatment for patients with cholestasis-associated pruritus (7, 8). More recently, nalfurafine hydrochloride, a selective κ-opioid receptor agonist, was approved in Japan for the treatment of refractory pruritus in patients with CLD (3, 9). Despite many opioid peptide-opioid receptor treatments used clinically to alleviate pruritus in CLD, no studies to date have demonstrated any significant correlation between endogenous opioid levels and the presence or intensity of pruritus. This study therefore evaluated the concentrations of β-endorphin (μ-opioid) and dynorphin A (κ-opioid) and their correlations with pruritus in CLD patients. ported no symptoms of pruritus. The 20 CLD patients were divided into two groups, 13 with and 7 without pruritus. We then examined the endogenous opioid levels between the controls and CLD patients with or without pruritus. The CLD patients with pruritus showed plasma concentrations of β-endorphin and β-endorphin/ dynorphin A ratio, which reflects the balance of endogenous opioids, to be significantly higher; while dynorphin A levels were significantly lower compared to the controls (Fig. 1). Importantly, a comparison of endogenous opioid levels showed that dynorphin A levels were significantly attenuated and β-endorphin/dynorphin A ratio significantly increased in CLD patients with pruritus than without. Notably, these levels were similar in the CLD patients without pruritus and the control group (Fig. 1b and c). Moreover, we examined the correlations among β-endorphin, dynorphin A, β-endorphin/dynorphin A ratio and VAS score. There was no correlation between β-endorphin level and VAS score (Fig. 2a). Meanwhile, dynorphin A level was negatively correlated and β-endorphin/dynorphin A ratio was positively correlated with the VAS score (Fig. 2b and c). DISCUSSION The present study showed that dynorphin A level and β-endorphin /dynorphin A ratio were consecutively at- tenuated and increased in plasma of CLD patients with pruritus compared to those without (Fig. 1), suggesting an imbalance of endogenous opioids in CLD patients with pruritus. In line with these findings, we discovered that dy- norphin A concentrations and the β-endorphin/dynorphin A ratio correlated significantly with the VAS scores in CLD patients (Fig. 2b and c). These findings suggest that plasma levels of endogenous opioids, especially dynorphin A, may objectively reflect the pruritus intensity in CLD patients. The endogenous opioid system has been shown to play a role in the mediation of pruritus of central origin (10) as well as in the periphery (4). Clinical and experimental MATERIALS AND METHODS ( see Appendix S1 1 ) RESULTS Clinical observations showed that, although pruritus occurs fre- quently in patients with CLD, some patients in the CLD group re- b 40 *** 20 15 10 5 0 Control Pruritus (-) Pruritus (+) * 30 c ** 20 10 0 doi: 10.2340/00015555-3139 Acta Derm Venereol 2019; 99: 442–443 Control Pruritus (-) https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3139 1 25 a Accepted Feb 5, 2019; E-published Feb 6, 2019 Pruritus (+) *** 2.0 * 1.5 1.0 0.5 0 Control Pruritus (-) Pruritus (+) Fig. 1. Relationships of β-endorphin and dynorphin A concentrations and β-endorphin/dynorphin A ratios with pruritus in chronic liver disease (CLD) patients. Twenty patients with CLD were divided into those with (n  = 13) and without (n  = 7) pruritus and the concentrations of β-endorphin (a) and dynorphin A (b) and β-endorphin/ dynorphin A ratios (c) were determined. *p  < 0.05, **p  < 0.01, ***p  < 0.001. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.