Orita Sumihisa, Ishikawa Tetsuhiro, Miyagi Masayuki, Ochiai Nobuyasu, Inoue Gen, Eguchi Yawara, Kamoda Hiroto, Arai Gen, Suzuki Miyako, Sakuma Yoshihiro, Oikawa Yasuhiro, Toyone Tomoaki, Aoki Yasuchika, Takahashi Kazuhisa, Ohtori Seiji
Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
J Orthop Sci. 2012 Jan;17(1):77-86. doi: 10.1007/s00776-011-0175-7. Epub 2011 Nov 26.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical situations to reduce inflammation and pain. Percutaneous administration is one of the routes mainly used in Japan to deal with the pain from acute injuries, to chronic pain such as chronic low back pain and osteoarthritis (OA). There have been no studies that report the effect of percutaneous administration of NSAIDs on chronic pain in animal models. This study aimed to investigate the effect of percutaneously absorbed NSAIDs on a rodent model of OA.
OA was induced with an intra-articular injection of monoiodoacetate into the right knees (left knee was treated with saline, normal control) of female Sprague-Dawley rats. Physical evaluation, diameter, and the range of motion (ROM) of the knee joint, as well as pain-related behavior, were evaluated. Animals were killed and perfused 7 days after the intra-articular injection, and then local tissue from the knee [for cytokine assay: tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF)] and spinal cord (immunostained for c-Fos protein reflecting neuronal excitation) were evaluated (n = 7 each). Twenty-eight days after the injection, the other rats were then divided into three groups and were identified by a plaster tape containing an NSAID or a vehicle applied to their OA (ipsilateral) knees: a vehicle-treated group, a loxoprofen-treated (lox) group, and a ketoprofen-treated (ket) group. The behavior elicited by von Frey hairs, inflammatory cytokines, and c-Fos protein at 0, 8, and 24 h after tape application were evaluated (n = 7 each). The plaster tapes contained corresponding NSAIDs used in clinical settings: lox 2.8 mg and ket 1.1 mg. Three of the OA animals were histologically evaluated.
As the OA progressed, the ipsilateral knee joint showed OA-like appearance physically and histologically. The knee diameter increased and ROM decreased significantly (P < 0.05), showing histological OA-like cartilage degeneration. Pain threshold decreased significantly according to OA progression (P < 0.05). NSAID application significantly improved the threshold 24 h after application in both the lox and ket groups (P < 0.05) without any significant difference between groups. Cytokine concentrations and c-Fos were significantly suppressed in both lox and ket groups (P < 0.05). Lox suppressed TNF-α and NGF more than ket, whereas ket suppressed IL-6 more.
Suppression of proinflammatory cytokines and c-Fos expression by clinically used NSAIDs suggests that their percutaneous administration may have an analgesic effect for treating chronic pain at a molecular level.
非甾体抗炎药（NSAIDs）常用于临床以减轻炎症和疼痛。经皮给药是日本处理急性损伤疼痛以及慢性疼痛（如慢性腰痛和骨关节炎（OA））的主要途径之一。尚无研究报道NSAIDs经皮给药对动物模型慢性疼痛的影响。本研究旨在探讨经皮吸收的NSAIDs对OA啮齿动物模型的影响。
通过向雌性Sprague-Dawley大鼠右膝关节腔内注射单碘乙酸诱导OA（左膝用生理盐水处理，作为正常对照）。评估膝关节的物理状态、直径、活动范围（ROM）以及疼痛相关行为。关节腔内注射7天后处死动物并进行灌注，然后评估膝关节局部组织[用于细胞因子检测：肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和神经生长因子（NGF）]和脊髓（对反映神经元兴奋的c-Fos蛋白进行免疫染色）（每组n = 7）。注射28天后，将其他大鼠分为三组，通过在其OA（同侧）膝关节上粘贴含NSAID或赋形剂的胶布来区分：赋形剂处理组、洛索洛芬处理（lox）组和酮洛芬处理（ket）组。评估粘贴胶布后0、8和24小时用von Frey毛发诱发的行为、炎性细胞因子和c-Fos蛋白（每组n = 7）。胶布中含有临床使用的相应NSAIDs：洛索洛芬2.8 mg和酮洛芬1.1 mg。对三只OA动物进行组织学评估。
随着OA进展，同侧膝关节在物理和组织学上呈现出OA样外观。膝关节直径增加，ROM显著降低（P < 0.05），显示出组织学上OA样软骨退变。随着OA进展，疼痛阈值显著降低（P < 0.05）。应用NSAIDs后24小时，lox组和ket组的阈值均显著改善（P < 0.05），两组之间无显著差异。lox组和ket组的细胞因子浓度和c-Fos均显著受到抑制（P < 0.05）。洛索洛芬对TNF-α和NGF的抑制作用大于酮洛芬，而酮洛芬对IL-6的抑制作用更强。
临床使用的NSAIDs对促炎细胞因子和c-Fos表达的抑制表明，其经皮给药可能在分子水平上对治疗慢性疼痛具有镇痛作用。
