Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms.
Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms.
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DOI：
10.1097/01.j.pain.0000460333.79127.be
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发表时间：
2015-03
期刊：
影响因子：
7.4
通讯作者：
Taylor BK
中科院分区：
文献类型：
--
作者：
Griggs RB;Donahue RR;Morgenweck J;Grace PM;Sutton A;Watkins LR;Taylor BK
重复给予过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可减少神经性疼痛样行为和脊髓背角神经胶质细胞活化的相关变化。由于PPARγ是一种核受体，基因表达的持续变化被广泛认为是疼痛减轻的机制。然而，我们最近报道，单次鞘内注射吡格列酮（一种PPARγ激动剂）可在30分钟内减少痛觉过敏，这一时间范围通常小于基因组机制所需的时间。为了确定PPARγ激活的非常快速的抗痛觉过敏作用，我们对保留神经损伤（SNI）大鼠给予吡格列酮并评价痛觉过敏。吡格列酮在注射后5分钟内抑制痛觉过敏，与非基因组机制一致。全身或鞘内给予GW9662（一种PPARγ拮抗剂）可抑制腹膜内或鞘内给予吡格列酮的抗痛觉过敏作用，提示脊髓PPARγ依赖性机制。为了进一步解决非基因组机制的贡献，我们用茴香霉素阻断了脊髓中新的蛋白质合成。当鞘内联合给药时，茴香霉素在早期7.5 min时间点未改变吡格列酮的抗痛觉过敏作用，进一步支持了快速非基因组机制。在以后的时间点，茴香霉素减少吡格列酮抗痛觉过敏，表明基因组机制的延迟招募。吡格列酮降低SNI诱导的GFAP表达增加的速度比预期的要快，在60分钟内。我们首次表明脊髓PPARγ的激活可以快速降低神经性疼痛，而不依赖于典型的基因组活性。我们的结论是，急性吡格列酮抑制神经病理性疼痛部分通过减少星形胶质细胞活化，并通过基因组和非基因组的过氧化物酶体增殖物激活受体γ机制。
Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid anti-hyperalgesic actions of PPARγ activation we administered pioglitazone to rats with spared nerve injury (SNI) and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 min of injection, consistent with a non-genomic mechanism. Systemic or intrathecal administration of GW9662, a PPARγ antagonist, inhibited the anti-hyperalgesic actions of intraperitoneal or intrathecal pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of non-genomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When co-administered intrathecally, anisomycin did not change pioglitazone anti-hyperalgesia at an early 7.5 min timepoint, further supporting a rapid non-genomic mechanism. At later timepoints anisomycin reduced pioglitazone anti-hyperalgesia, suggesting a delayed recruitment of genomic mechanisms. Pioglitazone reduction of SNI-induced increases in GFAP expression occurred more rapidly than expected, within 60 min. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent from canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation, and via both genomic and non-genomic PPARγ mechanisms.
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DOI：
10.1016/j.jpain.2009.09.008
发表时间：
2010-04
期刊：
The journal of pain
影响因子：
--
作者：
Corder G;Siegel A;Intondi AB;Zhang X;Zadina JE;Taylor BK
通讯作者：
Taylor BK
影响因子：
--
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
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