Ha Eunyoung, Lho Yun-Mee, Seo Hyuk-Jun, Cho Chul-Hyun
Departments of Biochemistry (E.H. and Y.-M. L.) and Orthopedic Surgery (H.-J. S. and C.-H.C.), Dongsan Medical Center, School of Medicine, Keimyung University, 56 Dalseong-ro, Jung-gu, Daegu 700-712, Republic of Korea. E-mail address for C.-H. Cho:
J Bone Joint Surg Am. 2014 Jul 2;96(13):e108. doi: 10.2106/JBJS.M.01011.
Nocturnal pain is commonly observed in patients with shoulder disorders such as a rotator cuff tear or frozen shoulder. This study was conducted to explore the possibility that melatonin plays a role as a mediator of nocturnal pain in patients with a rotator cuff tear or frozen shoulder.
Subacromial bursa and joint capsule samples were collected from sixty-three patients: twenty-one patients with a rotator cuff tear, twenty-two with frozen shoulder, and twenty with shoulder instability (control group). The expression of melatonin receptor 1A (MTNR1A) and 1B (MTNR1B) and of acid-sensing ion channel 3 (ASIC3) in the subacromial bursa and the joint capsule were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. The protein level of ASIC3 was measured by immunoblot analysis. To determine the effect of melatonin as a pain mediator, an in vitro study with use of primary cultured fibroblast-like synoviocytes was performed by semiquantitative RT-PCR analysis, immunoblot analysis, and enzyme-linked immunosorbent assay (ELISA).
MTNR1A, MTNR1B, and ASIC3 expression was significantly increased in both the rotator cuff tear and frozen shoulder groups compared with the control group of patients with shoulder instability. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) significantly stimulated the expression of MTNR1A and MTNR1B in primary cultured fibroblast-like synoviocytes treated with proinflammatory cytokines. Melatonin treatment at a physiological concentration (10 nM) induced ASIC3 expression and IL-6 production. Treatment with luzindole, a melatonin-receptor antagonist, reversed melatonin-stimulated ASIC3 expression and IL-6 production.
Our study suggests that melatonin may play a role as a mediator of nocturnal pain with a rotator cuff tear or frozen shoulder, and this effect may be mediated via melatonin receptors.
Melatonin may be a therapeutic target of chronotherapy.
夜间疼痛常见于患有肩袖撕裂或肩周炎等肩部疾病的患者。本研究旨在探讨褪黑素是否在肩袖撕裂或肩周炎患者的夜间疼痛中起介导作用。
从63例患者中采集肩峰下囊和关节囊样本：21例肩袖撕裂患者、22例肩周炎患者和20例肩部不稳定患者（对照组）。通过实时逆转录-聚合酶链反应（RT-PCR）分析确定肩峰下囊和关节囊中褪黑素受体1A（MTNR1A）和1B（MTNR1B）以及酸敏感离子通道3（ASIC3）的表达。通过免疫印迹分析测量ASIC3的蛋白水平。为了确定褪黑素作为疼痛介质的作用，使用原代培养的成纤维样滑膜细胞进行了体外研究，采用半定量RT-PCR分析、免疫印迹分析和酶联免疫吸附测定（ELISA）。
与肩部不稳定对照组相比，肩袖撕裂组和肩周炎组的MTNR1A、MTNR1B和ASIC3表达均显著增加。白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）显著刺激用促炎细胞因子处理的原代培养成纤维样滑膜细胞中MTNR1A和MTNR1B的表达。生理浓度（10 nM）的褪黑素处理诱导ASIC3表达和IL-6产生。褪黑素受体拮抗剂鲁辛朵治疗可逆转褪黑素刺激的ASIC3表达和IL-6产生。
我们的研究表明，褪黑素可能在肩袖撕裂或肩周炎的夜间疼痛中起介导作用，且这种作用可能通过褪黑素受体介导。
褪黑素可能是时间疗法的治疗靶点。
