Imhof Anne-Katja, Glück Laura, Gajda Mieczyslaw, Lupp Amelie, Bräuer Rolf, Schaible Hans-Georg, Schulz Stefan
University Hospital and Friedrich Schiller University Jena, Jena, Germany.
Arthritis Rheum. 2011 Aug;63(8):2352-62. doi: 10.1002/art.30410.
Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties. However, it is not known which of the 5 somatostatin receptor subtypes (SSTRs 1-5) is involved in these actions. The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide (SOM230) in a mouse model of antigen-induced arthritis (AIA).
Studies were performed in SSTR2-deficient mice (SSTR2(-/-)) and their wild-type littermates (SSTR2(+/+)). The expression of SSTR1, SSTR2A, SSTR3, and SSTR5 in dorsal root ganglia was examined by immunohistochemistry.
Untreated SSTR2(-/-) mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in SSTR2(+/+) mice. In wild-type mice, both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone. In SSTR2(-/-) mice, the antiinflammatory effects of both octreotide and pasireotide were completely abrogated. Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions. In addition, both octreotide and pasireotide reduced inflammatory hyperalgesia. The antinociceptive actions of octreotide were abolished in SSTR2(-/-) mice, but those of pasireotide were retained. In dorsal root ganglia of naive wild-type mice, only SSTR1 and SSTR2A, but not SSTR3 or SSTR5, were detected in a subset of small- and medium-diameter neurons.
Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the SSTR2 receptor. In addition, we identified the SSTR1 receptor as a novel pharmacologic target for somatostatin-mediated peripheral analgesia in inflammatory pain.
临床和临床前证据表明，生长抑素具有强大的抗炎和镇痛特性。然而，尚不清楚5种生长抑素受体亚型（SSTR1 - 5）中的哪一种参与了这些作用。本研究的目的是评估稳定的生长抑素类似物奥曲肽和帕瑞肽（SOM230）在抗原诱导性关节炎（AIA）小鼠模型中的作用。
在SSTR2基因缺陷小鼠（SSTR2(-/-)）及其野生型同窝小鼠（SSTR2(+/+)）中进行研究。通过免疫组织化学检测背根神经节中SSTR1、SSTR2A、SSTR3和SSTR5的表达。
未经治疗的患有AIA的SSTR2(-/-)小鼠表现出与SSTR2(+/+)小鼠相似的关节肿胀和机械性痛觉过敏。在野生型小鼠中，奥曲肽和帕瑞肽均能显著减轻膝关节肿胀和关节炎的组织病理学表现，其程度与地塞米松相当。在SSTR2(-/-)小鼠中，奥曲肽和帕瑞肽的抗炎作用完全消失。帕瑞肽的长期给药也能抑制关节肿胀，并在AIA发作反应期间防止关节破坏。此外，奥曲肽和帕瑞肽均能减轻炎症性痛觉过敏。奥曲肽的镇痛作用在SSTR2(-/-)小鼠中消失，但帕瑞肽的镇痛作用得以保留。在未接触过抗原的野生型小鼠的背根神经节中，仅在一小部分中小直径神经元中检测到SSTR1和SSTR2A，而未检测到SSTR3或SSTR5。
我们的研究结果表明，奥曲肽和帕瑞肽的镇痛和抗炎作用主要通过SSTR2受体介导。此外，我们将SSTR1受体确定为生长抑素介导的炎症性疼痛外周镇痛的新药理学靶点。
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