Malin Sacha A, Davis Brian M, Koerber Richard H, Reynolds Ian J, Albers Kathryn M, Molliver Derek C
Department of Medicine, University of Pittsburgh, Pittsburgh, S841 Scaife Hall, 3550 Terrace Avenue, PA 15261, USA Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA.
Pain. 2008 Sep 15;138(3):484-496. doi: 10.1016/j.pain.2008.01.026. Epub 2008 Mar 14.
Recent studies indicate that ATP and UTP act at G protein-coupled (P2Y) nucleotide receptors to excite nociceptive sensory neurons; nucleotides also potentiate signaling through the pro-nociceptive capsaicin receptor, TRPV1. We demonstrate here that P2Y(2) is the principal UTP receptor in somatosensory neurons: P2Y(2) is highly expressed in dorsal root ganglia and P2Y(2)-/- mice showed profound deficits in UTP-evoked calcium transients and potentiation of capsaicin responses. P2Y(2)-/- mice were also deficient in the detection of painful heat: baseline thermal response latencies were increased and mutant mice failed to develop thermal hypersensitivity in response to inflammatory injury (injection of complete Freund's adjuvant into the hindpaw). P2Y(2) was the only Gq-coupled P2Y receptor examined that showed an increase in DRG mRNA levels in response to inflammation. Surprisingly, TRPV1 function was also attenuated in P2Y(2)-/- mice, as measured by the frequency and magnitude of capsaicin responses in vitro and behavioral responses to capsaicin administration in vivo. However, TRPV1 mRNA levels and immunoreactivity were not reduced, and behavioral sensitivity to capsaicin could be largely restored in P2Y(2)-/- mice by pretreatment with bradykinin, suggesting that normal function of TRPV1 requires ongoing modulation by G protein-coupled receptors. These results indicate that nucleotide signaling through P2Y(2) plays a key role in thermal nociception.
近期研究表明，三磷酸腺苷（ATP）和尿苷三磷酸（UTP）作用于G蛋白偶联（P2Y）核苷酸受体，从而激活伤害性感觉神经元；核苷酸还可通过促伤害性辣椒素受体TRPV1增强信号传导。我们在此证明，P2Y(2)是躯体感觉神经元中的主要UTP受体：P2Y(2)在背根神经节中高度表达，且P2Y(2)基因敲除小鼠在UTP诱发的钙瞬变及辣椒素反应增强方面表现出严重缺陷。P2Y(2)基因敲除小鼠在疼痛热觉检测方面也存在缺陷：基线热反应潜伏期延长，且突变小鼠在受到炎性损伤（将完全弗氏佐剂注射到后爪）时未能产生热超敏反应。P2Y(2)是所检测的唯一一种与Gq偶联的P2Y受体，其在背根神经节中的信使核糖核酸（mRNA）水平会因炎症而升高。令人惊讶的是，通过体外辣椒素反应的频率和幅度以及体内辣椒素给药的行为反应来衡量，P2Y(2)基因敲除小鼠的TRPV1功能也减弱。然而，TRPV1的mRNA水平和免疫反应性并未降低，且通过缓激肽预处理，P2Y(2)基因敲除小鼠对辣椒素的行为敏感性可在很大程度上恢复，这表明TRPV1的正常功能需要G蛋白偶联受体的持续调节。这些结果表明，通过P2Y(2)的核苷酸信号传导在热痛觉中起关键作用。
