Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior.
Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior.
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DOI：
10.1186/1744-8069-6-21
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发表时间：
2010-04-15
期刊：
影响因子：
3.3
通讯作者：
Molliver DC
中科院分区：
文献类型：
--
作者：
Malin SA;Molliver DC
核苷酸信号传导在伤害性感受中的作用研究主要集中在三磷酸腺苷（ATP）的作用上。ATP门控离子通道（P2 X受体）和G蛋白偶联（P2 Y）受体都参与外周感觉神经元的伤害性信号传导。此外，一些研究表明，Gq偶联的二磷酸腺苷（ADP）受体P2 Y1在感觉转导。在这项研究中，我们研究了P2 Y1和Gi偶联受体P2 Y12，P2 Y13和P2 Y14在感觉神经元中的表达和功能，以确定它们对伤害感受的贡献。本实验检测了小鼠背根神经节（DRG）中ADP受体P2 Y12和P2 Y13的mRNA和蛋白表达。P2 Y14是一种同源的Gi偶联核苷酸受体，也在DRG中表达。受体分布的免疫组织化学分析表明，这些受体广泛表达于伤害性神经元。使用比率钙成像，我们发现，ADP引起的细胞内钙在隔离DRG神经元的增加，也产生了百日咳毒素敏感的抑制去极化诱发的钙瞬变。选择性P2 Y1拮抗剂MRS 2179的存在下，ADP的抑制作用是不变的，并在从P2 Y1基因敲除小鼠分离的神经元，而ADP诱发的钙瞬变大大减少。在炎性损伤之前和之后（将完全弗氏佐剂注射到后爪中）对有害热的行为反应的分析揭示，P2 Y1是炎性痛觉过敏的完全表达所需的，而局部注射用于Gi偶联的P2 Y受体的激动剂减少痛觉过敏。我们报告说，Gi偶联P2 Y受体广泛表达于外周感觉神经元。这些受体的激动剂抑制离体神经元中的伤害性信号传导并减少体内的行为痛觉过敏。这些受体的抗伤害作用似乎被Gq偶联ADP受体P2 Y1拮抗，这是炎症性痛觉过敏的充分表达所必需的。我们提出，伤害感受器的敏感性是通过整合核苷酸信号通过Gq-和Gi-偶联P2 Y受体调制的，这种平衡在响应炎症损伤时改变。综上所述，我们的数据表明，Gi偶联P2 Y受体广泛表达于伤害感受器中，抑制体内伤害性信号传导，并代表开发新型镇痛药物的潜在靶点。
Investigations of nucleotide signaling in nociception to date have focused on actions of adenosine triphosphate (ATP). Both ATP-gated ion channels (P2X receptors) and G protein-coupled (P2Y) receptors contribute to nociceptive signaling in peripheral sensory neurons. In addition, several studies have implicated the Gq-coupled adenosine diphosphate (ADP) receptor P2Y1 in sensory transduction. In this study, we examined the expression and function of P2Y1 and the Gi-coupled receptors P2Y12, P2Y13 and P2Y14 in sensory neurons to determine their contribution to nociception. We detected mRNA and protein for ADP receptors P2Y12 and P2Y13 in mouse dorsal root ganglia (DRG). P2Y14, a homologous Gi-coupled nucleotide receptor, is also expressed in DRG. Immunohistochemical analysis of receptor distribution indicated that these receptors are widely expressed in nociceptive neurons. Using ratiometric calcium imaging, we found that ADP evokes increases in intracellular calcium in isolated DRG neurons and also produces a pertussis toxin-sensitive inhibition of depolarization-evoked calcium transients. The inhibitory effect of ADP was unaltered in the presence of the selective P2Y1 antagonist MRS2179 and in neurons isolated from P2Y1 knockout mice, whereas ADP-evoked calcium transients were greatly reduced. Analysis of behavioral responses to noxious heat before and after inflammatory injury (injection of complete Freund's adjuvant into the hindpaw) revealed that P2Y1 is required for the full expression of inflammatory hyperalgesia, whereas local injection of agonists for Gi-coupled P2Y receptors reduced hyperalgesia. We report that Gi-coupled P2Y receptors are widely expressed in peripheral sensory neurons. Agonists for these receptors inhibit nociceptive signaling in isolated neurons and reduce behavioral hyperalgesia in vivo. Anti-nociceptive actions of these receptors appear to be antagonized by the Gq-coupled ADP receptor, P2Y1, which is required for the full expression of inflammatory hyperalgesia. We propose that nociceptor sensitivity is modulated by the integration of nucleotide signaling through Gq- and Gi-coupled P2Y receptors, and this balance is altered in response to inflammatory injury. Taken together, our data suggest that Gi-coupled P2Y receptors are broadly expressed in nociceptors, inhibit nociceptive signaling in vivo, and represent potential targets for the development of novel analgesic drugs.
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影响因子：
7.4
作者：
Malin, Sacha A.;Davis, Brian M.;Molliver, Derek C.
通讯作者：
Molliver, Derek C.
影响因子：
5.3
作者：
Gerevich, Z;Borvendeg, SJ;Illes, P
通讯作者：
Illes, P
影响因子：
3.4
作者：
Molliver, DC;Cook, SP;McCleskey, EW
通讯作者：
McCleskey, EW
影响因子：
7.4
作者：
Nandi, R;Beacham, D;Fitzgerald, M
通讯作者：
Fitzgerald, M
影响因子：
2.5
作者：
Kobayashi, Kimiko;Fukuoka, Tetsuo;Noguchi, Koichi
通讯作者：
Noguchi, Koichi