Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors
Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors
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DOI：
10.1073/pnas.1110460109
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发表时间：
2012-04-24
影响因子：
11.1
通讯作者：
Yaksh, Tony L.
中科院分区：
文献类型：
--
作者：
Gregus, Ann M.;Doolen, Suzanne;Yaksh, Tony L.
周围炎症引发脊髓伤害感受处理的变化，导致痛觉过敏。此前，我们证明，在大鼠脊髓中通过 LC-MS/MS 分析检测到的 102 种脂质中，足底内卡拉胶后发生的最显着的增加是 12-脂氧合酶 (12-LOX) 的代谢物，特别是肝素 (HXA(3) 和 HXB3)。因此，我们研究了脊髓 LOX 酶在炎症性痛觉过敏中的参与情况。在目前的工作中，我们发现鞘内（IT）递送LOX抑制剂去甲二氢愈创木酸可以防止角叉菜胶引起的脊髓HXB3增加，剂量可减弱相关的痛觉过敏。此外，IT 递送针对 12-LOX（CDC，黄芩素）而非 5-LOX（Zileuton）的抑制剂可剂量依赖性减弱触觉异常性疼痛。同样，IT 递送花生四烯酸 12(S)-HpETE、12(S)-HETE、HXA(3) 或 HXB3 的 12-LOX 代谢物会引起严重、持续的触觉异常性疼痛，但 12(S)-HpETE 和 HXA(3) 会产生相对温和的短暂热痛觉过敏。 HXA(3) 的伤害感受作用与初级感觉传入 P 物质释放的增强相关。重要的是，HXA(3) 触发了稳定过表达 TRPV1 或 TRPA1 受体的细胞以及急性分离的啮齿动物感觉神经元中钙的持续动员。 TRPV1 (AMG9810) 或 TRPA1 (HC030031) 的组成型缺失或拮抗剂会减弱这种作用。此外，用抗痛觉过敏剂量的 AMG9810 或 HC030031 进行预处理可减少脊髓 HXA(3) 诱发的异常性疼痛。这些数据表明脊髓 HXA(3) 因周围炎症而增加，并通过直接激活中央末端的 TRPV1 和 TRPA1 促进易化伤害性处理的启动。
Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB3). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB3 at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB3 evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.