Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation.
Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation.
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DOI：
10.3389/fnins.2017.00679
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发表时间：
2017
影响因子：
4.3
通讯作者：
Taylor BK
中科院分区：
文献类型：
--
作者：
Griggs RB;Laird DE;Donahue RR;Fu W;Taylor BK
甲基乙二醛（MG）是葡萄糖的代谢物，可能导致糖尿病患者周围神经病变和疼痛。MG增加感觉神经元细胞内钙，并通过阳离子通道瞬时受体电位锚蛋白1 （TRPA1）产生行为痛觉。然而，需要对甲基乙二醛诱发疼痛的动物模型进行严格的表征，包括测试甲基乙二醛是否会促进负面疼痛影响。此外，甲基乙二醛是否足以激活脊髓背角的神经元，这是否需要TRPA1，以及钙敏感的腺苷酸环化酶1异构体（AC1）是否有助于mg诱发的疼痛，这些都尚不清楚。我们给予足底甲基乙二醛，然后在野生型大鼠和小鼠以及TRPA1或AC1破坏后评估细胞外信号调节激酶（p-ERK）的免疫组织化学磷酸化和多种疼痛样行为。甲基乙二醛产生条件性场所回避（CPA）（一种情感性疼痛的测量方法）、剂量依赖性舔舐和举起伤害性行为、对热和机械刺激的痛觉过敏以及脊髓背角的p-ERK。TRPA1基因敲除或鞘内给予TRPA1拮抗剂（HC030031）可减轻甲基乙二醛诱发的p-ERK、痛觉和痛觉过敏。敲除AC1可消除痛觉过敏，但不能消除伤害性行为。这些结果表明，足底注射甲基乙二醛重现了糖尿病动物模型或糖尿病患者中发现的疼痛性糖尿病神经病变的多种迹象，包括脊髓损伤反应神经元的激活和TRPA1-AC1致敏机制的潜在参与。我们得出结论，MG的给药是研究MG- trpa1 - ac1通路的外周和中枢成分的有价值的模型，该通路有助于疼痛性糖尿病神经病变。
Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated immunohistochemical phosphorylation of extracellular signal-regulated kinase (p-ERK) and multiple pain-like behaviors in wild-type rats and mice and after disruption of either TRPA1 or AC1. Methylglyoxal produced conditioned place avoidance (CPA) (a measure of affective pain), dose-dependent licking and lifting nociceptive behaviors, hyperalgesia to heat and mechanical stimulation, and p-ERK in the spinal cord dorsal horn. TRPA1 knockout or intrathecal administration of a TRPA1 antagonist (HC030031) attenuated methylglyoxal-evoked p-ERK, nociception, and hyperalgesia. AC1 knockout abolished hyperalgesia but not nociceptive behaviors. These results indicate that intraplantar administration of methylglyoxal recapitulates multiple signs of painful diabetic neuropathy found in animal models of or patients with diabetes, including the activation of spinal nociresponsive neurons and the potential involvement of a TRPA1-AC1 sensitization mechanism. We conclude that administration of MG is a valuable model for investigating both peripheral and central components of a MG-TRPA1-AC1 pathway that contribute to painful diabetic neuropathy.
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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：
25
作者：
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影响因子：
2.5
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影响因子：
7.3
作者：
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影响因子：
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作者：
Griggs RB;Donahue RR;Morgenweck J;Grace PM;Sutton A;Watkins LR;Taylor BK
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Taylor BK