The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin
The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin
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DOI：
10.1073/pnas.0603861103
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发表时间：
2006-07-25
影响因子：
11.1
通讯作者：
Hargreaves, Kenneth M.
中科院分区：
文献类型：
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作者：
Patwardhan, Amol M.;Jeske, Nathaniel A.;Hargreaves, Kenneth M.
大麻素可以在外周作用部位引起抗痛觉过敏和抗伤害感受。然而，介导这些效应的信号通路尚不清楚。我们测试的假设，某些大麻素直接抑制外周辣椒素敏感的伤害性神经元通过去磷酸化和脱敏瞬时受体电位香草醛1（TRPV 1）通过钙钙依赖性机制。将大麻素WIN 55，212 -2（WIN）应用于培养的三叉神经（TG）神经元或分离的皮肤活组织检查，通过需要细胞外钙存在的机制，快速且显著地抑制辣椒素激活的内向电流和神经肽胞吐。抑制作用不涉及G蛋白偶联大麻素受体的活化，因为百日咳毒素和GDP β S处理都不改变WIN效应。然而，通过活化T细胞核因子（NFAT）c4转录因子的核转位测量，应用WIN-activated钙调磷酸酶使TRPV 1去磷酸化。WIN-induced脱敏的TRPV 1介导的钙调磷酸酶，因为结构不同的钙调磷酸酶拮抗剂（钙调磷酸酶自抑制肽和环孢素/亲环素复合物）的应用取消了WIN-induced抑制辣椒素诱发的内向电流和神经肽胞吐。这种机制也有助于外周抗伤害/抗痛觉过敏的WIN的影响，因为预处理与钙调神经磷酸酶拮抗剂钙调神经磷酸酶自抑制肽（CAIP）显着降低外周介导的WIN的影响，在两个行为模型。总的来说，这些数据表明大麻素如WIN通过钙调磷酸酶途径直接抑制TRPV 1功能活性，该途径代表大麻素在外周部位的作用机制。
Cannabinoids can evoke antihyperalgesia and antinociception at a peripheral site of action. However, the signaling pathways mediating these effects are not clearly understood. We tested the hypothesis that certain cannabinoids directly inhibit peripheral capsaicin-sensitive nociceptive neurons by dephosphorylating and desensitizing transient receptor potential vanilloid 1 (TRPV1) via a calcium calcineurin-dependent mechanism. Application of the cannabinoid WIN 55,212-2 (WIN)to cultured trigeminal (TG) neurons or isolated skin biopsies rapidly and significantly inhibited capsaicin-activated inward currents and neuropeptide exocytosis by a mechanism requiring the presence of extracellular calcium. The inhibitory effect did not involve activation of G protein-coupled cannabinoid receptors, because neither pertussis toxin nor GDP beta S treatments altered the WIN effect. However, application of WIN-activated calcineurin, as measured by nuclear translocation of the nuclear factor of activated T cells (NFAT)c4 transcription factor, dephosphorylated TRPV1. The WIN-induced desensitization of TRPV1 was mediated by calcineurin, because the application of structurally distinct calcineurin antagonists (calcineurin autoinhibitory peptide and cyclosporine/cyclophilin complex) abolished WIN-induced inhibition of capsaicin-evoked inward currents and neuropeptide exocytosis. This mechanism also contributed to peripheral antinociceptive/antihyperalgesic effects of WIN because pretreatment with the calcineurin antagonist calcineurin autoinhibitory peptide (CAIP) significantly reduced peripherally mediated WIN effects in two behavioral models. Collectively, these data demonstrate that cannabinoids such as WIN directly inhibit TRPV1 functional activities via a calcineurin pathway that represents a mechanism of cannabinoid actions at peripheral sites.