Wang Hui-Jing, Gu Han-Xin, Eijkelkamp Niels, Heijnen Cobi J, Kavelaars Annemieke
Laboratory of Neuropsychopharmacology, College of Fundamental Medicine, Shanghai University of Medicine & Health Science, Shanghai, China.
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, Netherlands.
Front Pharmacol. 2018 Jun 5;9:592. doi: 10.3389/fphar.2018.00592. eCollection 2018.
We recently identified the balance between the level of G protein coupled receptor kinase 2 (GRK2) and Epac1 in nociceptors as a key factor in the transition from acute to chronic pain that occurs in mice 'primed' by an inflammatory stimulus. Here, we examined the contribution of GRK2 and Epac-signaling to growth factor-induced hyperalgesic priming. Mice were primed by intraplantar injection with glial cell-derived neurotrophic factor (GDNF). Mechanical allodynia in response to PGE was followed over time in primed and non-primed animals. GRK2 protein levels in dorsal root ganglion (DRG) neurons were quantified by immunohistochemistry. The effect of herpes simplex virus (HSV)-GRK2 amplicons to restore GRK2 levels or of an Epac inhibitor on PGE allodynia in primed mice was examined. Glial cell-derived neurotrophic factor-induced hyperalgesia disappeared within 12 days. The hyperalgesic response to a subsequent intraplantar injection of PGE was prolonged from <24 h in control mice to more than 72 h in GDNF-primed mice. In male and female primed mice, PGE hyperalgesia was inhibited by oral administration of the Epac inhibitor ESI-09, while the drug had no effect in control mice. Mice primed with GDNF had reduced levels of GRK2 in IB4(+) small DRG neurons, but normal GRK2 levels in IB4(-) DRG neurons. Intraplantar administration of HSV-GRK2 amplicons to increase GRK2 protein levels prevented the prolongation of PGE-induced hyperalgesia in GDNF-primed mice. Low GRK2 in nociceptors is critical to develop a primed state in response to GDNF and leads to engagement of Epac signaling and transition to chronic PGE-induced hyperalgesia. Increasing GRK2 protein or inhibiting Epac signaling may represent new avenues for preventing transition to a chronic pain state.
我们最近发现，伤害感受器中G蛋白偶联受体激酶2（GRK2）水平与环磷腺苷效应元件结合蛋白激活肽1（Epac1）之间的平衡，是由炎症刺激“引发”的小鼠从急性疼痛转变为慢性疼痛过程中的关键因素。在此，我们研究了GRK2和Epac信号传导对生长因子诱导的痛觉过敏引发的作用。通过足底注射胶质细胞源性神经营养因子（GDNF）使小鼠致敏。随着时间的推移，观察致敏和未致敏动物对前列腺素E（PGE）产生的机械性异常性疼痛。通过免疫组织化学法定量背根神经节（DRG）神经元中的GRK2蛋白水平。研究单纯疱疹病毒（HSV）-GRK2扩增子恢复GRK2水平的作用，或Epac抑制剂对致敏小鼠PGE异常性疼痛的影响。胶质细胞源性神经营养因子诱导的痛觉过敏在12天内消失。对随后足底注射PGE的痛觉过敏反应，在对照小鼠中持续时间小于24小时，而在GDNF致敏小鼠中延长至超过72小时。在雄性和雌性致敏小鼠中，口服Epac抑制剂ESI-09可抑制PGE痛觉过敏，而该药物对对照小鼠无作用。用GDNF致敏的小鼠，IB4（+）小DRG神经元中的GRK2水平降低，但IB4（-）DRG神经元中的GRK2水平正常。足底注射HSV-GRK2扩增子以增加GRK2蛋白水平，可防止GDNF致敏小鼠中PGE诱导的痛觉过敏延长。伤害感受器中低水平的GRK2对于响应GDNF形成致敏状态至关重要，并导致Epac信号传导的激活以及向慢性PGE诱导的痛觉过敏的转变。增加GRK2蛋白或抑制Epac信号传导可能是预防转变为慢性疼痛状态的新途径。
