Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America.
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
PLoS One. 2019 Feb 27;14(2):e0211349. doi: 10.1371/journal.pone.0211349. eCollection 2019.
Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist-capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.
理解痛觉过敏状态是如何在最初的几小时到几天之后发展和持续的，对于设计预防和/或逆转慢性痛觉过敏状态的策略至关重要。伤害感受器转录的变化可以改变伤害性信号元素的丰度，导致伤害感受器表型的长期变化。因此，致敏的伤害性信号可以进一步放大，伤害性行为可以持续数周到数月。基于我们之前的发现，转录因子 Sp4 正向调节背根神经节（DRG）神经元中疼痛转导通道 TRPV1 的表达，我们试图确定 Sp4 是否在小鼠的超敏状态的发展和持续中发挥更广泛的作用。我们观察到，超过 90%的 Sp4 染色的 DRG 神经元是中小大小的，主要是非髓鞘（NF200 neg），并且大多数共同表达伤害感受器标记物 TRPV1 和/或异硫氰酸荧光素 B4（IB4）。Sp4 表达减少 50%的基因修饰小鼠（Sp4+/-）显示 DRG TRPV1 mRNA 减少，并且对 TRPV1 激动剂辣椒素的神经元反应减少。重要的是，Sp4+/- 小鼠未能发展出持续性炎症性热痛觉过敏，在 6 小时后恢复到对照值。尽管炎症性热痛觉过敏得到逆转，但在 CFA Sp4+/- 和 CFA 野生型小鼠之间，CFA 诱导的后爪肿胀没有差异。同样，Sp4+/- 小鼠对 NGF 后爪注射也未能发展出持续性机械性超敏反应。虽然 Sp4+/- 小鼠对创伤性神经损伤产生了超敏反应，但 Sp4+/- 小鼠未能对铂类化疗药物奥沙利铂产生持续性冷或机械超敏反应，奥沙利铂是一种非创伤性神经病理性疼痛模型。总的来说，Sp4+/- 小鼠表现出逆转多种持续性炎症和神经病理性超敏反应模型发展的显著能力。这表明 Sp4 作为一个关键的控制点，控制着参与痛觉过敏状态持续存在的基因网络。
