Payrits Maja, Sághy Éva, Cseko Kata, Pohóczky Krisztina, Bölcskei Kata, Ernszt Dávid, Barabás Klaudia, Szolcsányi János, Ábrahám István M, Helyes Zsuzsanna, Szoke Éva
Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, H-7624 Pécs, Hungary.
Janos Szentagothai Research Centre, University of Pécs, H-7624 Pécs, Hungary.
Endocrinology. 2017 Oct 1;158(10):3249-3258. doi: 10.1210/en.2017-00101.
Sex differences exist in chronic pain pathologies, and gonadal estradiol (E2) alters the pain sensation. The nocisensor transient receptor potential vanilloid 1 (TRPV1) receptor plays a critical role in triggering pain. Here we examined the impact of E2 on the function of TRPV1 receptor in mice sensory neurons in vitro and in vivo. Both mechano- and thermonociceptive thresholds of the plantar surface of the paw of female mice were significantly lower in proestrus compared with the estrus phase. These thresholds were higher in ovariectomized (OVX) mice and significantly lower in sham-operated mice in proestrus compared with the sham-operated mice in estrus phase. This difference was absent in TRPV1 receptor-deficient mice. Furthermore, E2 potentiated the TRPV1 receptor activation-induced mechanical hyperalgesia in OVX mice. Long pretreatment (14 hours) with E2 induced a significant increase in TRPV1 receptor messenger RNA expression and abolished the capsaicin-induced TRPV1 receptor desensitization in primary sensory neurons. The short E2 incubation (10 minutes) also prevented the desensitization, which reverted after coadministration of E2 and the tropomyosin-related kinase A (TrkA) receptor inhibitor. Our study provides in vivo and in vitro evidence for E2-induced TRPV1 receptor upregulation and sensitization mediated by TrkAR via E2-induced genomic and nongenomic mechanisms. The sensitization and upregulation of TRPV1 receptor by E2 in sensory neurons may explain the greater pain sensitivity in female mice.
慢性疼痛病理存在性别差异，性腺雌激素（E2）会改变痛觉。伤害感受器瞬时受体电位香草酸亚型1（TRPV1）受体在引发疼痛中起关键作用。在此，我们在体外和体内研究了E2对小鼠感觉神经元中TRPV1受体功能的影响。与发情期相比，处于动情前期的雌性小鼠爪足底表面的机械性和热伤害感受阈值显著更低。这些阈值在去卵巢（OVX）小鼠中更高，而在动情前期假手术小鼠中与处于发情期的假手术小鼠相比显著更低。这种差异在TRPV1受体缺陷小鼠中不存在。此外，E2增强了OVX小鼠中TRPV1受体激活诱导的机械性痛觉过敏。用E2进行长时间预处理（14小时）可导致TRPV1受体信使核糖核酸表达显著增加，并消除辣椒素诱导的初级感觉神经元中TRPV1受体脱敏。短暂的E2孵育（十分钟）也可防止脱敏，在同时给予E2和原肌球蛋白相关激酶A（TrkA）受体抑制剂后这种脱敏恢复。我们的研究提供了体内和体外证据，证明E2通过TrkAR介导的基因组和非基因组机制诱导TRPV1受体上调和致敏。E 在感觉神经元中对TRPV1受体的致敏和上调可能解释了雌性小鼠中更高的疼痛敏感性。 2
