Differential Antiinflammatory and Antinociceptive Effects of the Somatostatin Analogs Octreotide and Pasireotide in a Mouse Model of Immune-Mediated Arthritis
Differential Antiinflammatory and Antinociceptive Effects of the Somatostatin Analogs Octreotide and Pasireotide in a Mouse Model of Immune-Mediated Arthritis
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DOI：
10.1002/art.30410
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发表时间：
2011-08-01
影响因子：
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通讯作者：
Schulz, Stefan
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文献类型：
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作者：
Imhof, Anne-Katja;Glueck, Laura;Schulz, Stefan
Objective.临床和临床前证据表明，生长抑素表现出强有力的镇痛和抗伤害性。然而，尚不清楚5种生长抑素受体亚型（SSTR 1-5）中的哪一种参与这些作用。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（SOM 230）在抗原诱导的关节炎（AIA）小鼠模型中的作用。在SSTR 2缺陷型小鼠（SSTR 2（-/-））及其野生型同窝小鼠（SSTR 2（+/+））中进行研究。采用免疫组织化学方法检测大鼠背根神经节中SSTR 1、SSTR 2A、SSTR 3和SSTR 5的表达。AIA未处理的SSTR 2（-/-）小鼠显示出与SSTR 2（+/+）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SSTR 2（-/-）小鼠中，奥曲肽和帕瑞肽的抑制作用完全消失。帕瑞肽的长期给药也抑制了关节肿胀，并防止AIA发作反应期间的关节破坏。此外，奥曲肽和帕瑞肽都能减少炎性痛觉过敏。在SSTR 2（-/-）小鼠中，奥曲肽的抗伤害性作用被取消，但帕瑞肽的抗伤害性作用被保留。在野生型小鼠背根神经节中，只有SSTR 1和SSTR 2A在小直径和中等直径的神经元中表达，而SSTR 3和SSTR 5则未表达。我们的研究结果表明，奥曲肽和帕瑞肽的抗伤害和镇痛作用主要是通过SSTR 2受体介导的。此外，我们确定了SSTR 1受体作为一种新的药理学靶点生长抑素介导的外周镇痛炎性疼痛。
Objective. 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).Methods. Studies were performed in SSTR2-deficient mice (SSTR2(-/-)) and their wild-type litter-mates (SSTR2(+/+)). The expression of SSTR1, SSTR2A, SSTR3, and SSTR5 in dorsal root ganglia was examined by immunohistochemistry.Results. 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.Conclusion. Our findings indicate that the anti-nociceptive 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.