The cytochrome P450 inhibitor, ketoconazole, inhibits oxidized linoleic acid metabolite-mediated peripheral inflammatory pain.
The cytochrome P450 inhibitor, ketoconazole, inhibits oxidized linoleic acid metabolite-mediated peripheral inflammatory pain.
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细胞色素P450抑制剂酮康唑抑制氧化的亚油酸代谢物介导的外周炎性疼痛。
DOI：
10.1186/1744-8069-8-73
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发表时间：
2012-09-24
期刊：
影响因子：
3.3
通讯作者：
Hargreaves KM
中科院分区：
文献类型：
--
作者：
Ruparel S;Green D;Chen P;Hargreaves KM
氧化亚油酸代谢物（OLAMs）是一类瞬时受体电位V1（TRPV 1）受体的内源性激动剂。虽然TRPV 1介导炎性热痛觉过敏，但尚不清楚OLAMs是否有助于组织炎症期间该受体的外周激活。在本研究中，我们评估了OLAM系统是否在炎症过程中被激活，以及细胞色素P450酶是否介导OLAM对使用完全弗氏佐剂（CFA）炎症模型的热痛觉过敏的贡献。我们的结果表明，足底（ipl）注射抗OLAM抗体显着逆转CFA诱导的热痛觉过敏。此外，应用从发炎大鼠皮肤的脂质提取物培养的感觉神经元触发了iCGRP的显着释放，这是通过与I-RTX，TRPV 1拮抗剂的共同治疗阻断。为了确定β-内酰胺酶在介导OLAM效应中的作用，我们使用了广谱β-内酰胺酶抑制剂酮康唑。用酮康唑预处理可抑制炎症皮肤脂质提取物中TRPV 1激动剂的释放，并通过外周作用机制显著逆转CFA诱导的热痛觉过敏。此外，在CFA后24小时向大鼠ipl注射亚油酸诱发自发性伤害性行为，辣椒平、TRPV 1基因敲除或抗OLAM抗体或酮康唑预处理可显著降低自发性伤害性行为。两者合计，我们的数据表明，OLAMs有助于在外周的炎症性伤害感受，细胞色素P450酶在介导OLAM对炎症性热痛觉过敏的贡献中起着至关重要的作用。
Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous agonists to the transient receptor potential V1 (TRPV1) receptor. Although TRPV1 mediates inflammatory heat hyperalgesia, it is not known if the OLAMs contribute to the peripheral activation of this receptor during tissue inflammation. In the present study, we evaluated whether the OLAM system is activated during inflammation and whether cytochrome P450 enzymes mediate OLAM contributions to heat hyperalgesia using the complete Freund’s adjuvant (CFA) model of inflammation. Our results demonstrate that the intraplantar (ipl) injection of anti-OLAM antibodies significantly reversed CFA-induced heat hyperalgesia. Moreover, application of lipid extracts from inflamed rat skin to cultured sensory neurons triggered a significant release of iCGRP that is blocked by co-treatment with I-RTX, a TRPV1 antagonist. To determine the role of CYP enzymes in mediating OLAM effects, we used a broad spectrum CYP inhibitor, ketoconazole. Pretreatment with ketoconazole inhibited the release of TRPV1 agonists in lipid extracts from inflamed skin and significantly reversed CFA-induced heat hyperalgesia by a peripheral mechanism of action. Moreover, the ipl injection of linoleic acid to rats 24 hr after CFA evoked spontaneous nocifensive behaviors that were significantly reduced by capsazepine, by knockout of the TRPV1 gene, or by pretreatment with either anti-OLAM antibodies or ketoconazole. Taken together, our data suggests that OLAMs contribute to inflammatory nociception in the periphery and that cytochrome P450 enzymes play a crucial role in mediating OLAM contributions to inflammatory heat hyperalgesia.
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影响因子：
4.7
作者：
Iliff JJ;Fairbanks SL;Balkowiec A;Alkayed NJ
通讯作者：
Alkayed NJ
影响因子：
7.4
作者：
Ruparel S;Henry MA;Akopian A;Patil M;Zeldin DC;Roman L;Hargreaves KM
通讯作者：
Hargreaves KM
影响因子：
5.8
作者：
Bratland, Eirik;Skinningsrud, Beate;Husebye, Eystein S.
通讯作者：
Husebye, Eystein S.
影响因子：
15.9
作者：
Patwardhan, Amol M.;Akopian, Armen N.;Hargreaves, Kenneth M.
通讯作者：
Hargreaves, Kenneth M.
DOI：
10.1073/pnas.0905415106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Patwardhan, Amol M.;Scotland, Phoebe E.;Hargreaves, Kenneth M.
通讯作者：
Hargreaves, Kenneth M.