P2X_3和P2Y_1受体参与雌激素调节外周痛觉转导及机制研究
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摘要
目的:本课题旨在研究初级感觉传入神经元上P2X_3和P2Y_1受体是否参与了雌激素对外周痛觉的调节及其中的机制。方法:采用痛阈测定、免疫组化、电生理学和分子生物学等技术,在假手术、去性腺和雌激素替代的大鼠,观察了背根神经节P2X_3和P2Y_1受体的表达以及P2X_3受体功能的变化。结果:大鼠去卵巢后皮肤机械性痛阈明显降低,热痛阈增高。而大鼠去睾丸后机械性痛阈和热痛阈均无明显改变。雌激素替代后机械性痛阈增高,而热痛阈降低。大鼠去卵巢后腰骶段DRG中P2X_3mRNA明显增加,P2Y_1mRNA显著降低,雌激素替代后恢复。在DRG分离培养的细胞,17β-雌二醇可以通过其受体,明显抑制P2X_3mRNA,增加P2Y_1mRNA。17β-雌二醇还可以通过其受体,快速抑制DRGP2X_3受体介导的瞬时型电流,呈剂量依赖性,PKA和PKC途径参与了这一过程。在结肠炎大鼠,腰骶段DRG和结肠中P2X_3mRNA明显高于对照组,而与单独去卵巢组相比,去卵巢后致结肠炎的大鼠,P2X_3mRNA在结肠中明显减少,但DRG中未见明显改变。在结肠炎大鼠的DRG细胞上,17β-雌二醇可以快速调节ATP诱导的内向型电流。
结论:雌激素可以通过基因组机制和非基因组机制,调节初级感觉传入神经元P2X_3和P2Y_1受体,从而对正常和炎症时外周痛觉信号转导和传递起到重要的作用。
OBJECTIVE: This investigation was undertaken to determine whether the sensory neuron adenosine tnphosphate receptor subunit (P2X_3 and P2Y_1) are involved in modulatory function by estrogen in the peripheral pain transduction in dorsal root ganglia. METHODS: Peripheral pain threshold test, real-time quantitative reverse transcription-polymerase chain reaction analysis, immunohistochemical methods and patch clamp recording were used to determine the mean relative concentrations of the P2X_3 and P2Y_1 receptor in rat dorsal root ganglia in Sham-OP, GDX and E_2-R rats. RESULTS: The peripheral mechanical and thermal pain threshold was decreased and increased respectively after ovariectomy in female rats, while both of them didn't alter significantly after orchiectomy in male rats. The mechanical and thermal pain threshold was increased and decreased significantly after gonadectomy with estradiol replacement. P2X_3mRNA expression was significantly increased while P2Y| mRNA expression wasdecreased after surgical ovariectomy and both were reversed after estrogen replacement. In the cultured DRG neurons, P2X_3 mRNA and P2Y_1 mRNA was significantly decreased and increased respectively 24hrs after application of 17β-estradiol in a concentration dependent manner, which was through estrogen receptors. 17β-estradiol also rapidly inhibited P2X_3 mediated transient current in DRG neurons, with PKA and PKC pathways involved. In colitis rat, P2X_3 mRNA in DRG and colon was significantly increased comparing with those from control group. While in colitis rat after ovariectomy, P2X_3 mRNA in colon but not in DRG was significantly increased comparing with that from OVX group. In DRG cells from colitis rats, 17β-estradiol modulated ATP induced inward currents. CONCLUSIONS: These results suggest that the female gonadal hormone, 17β-estradiol, might participate in control of peripheral pain signal transduction in normal and colitis rats, by modulating P2X_3 and P2Y_1 receptor-mediated events in primary sensory neurons, through non-genomic and genomic mechanisms.
结论:雌激素可以通过基因组机制和非基因组机制,调节初级感觉传入神经元P2X_3和P2Y_1受体,从而对正常和炎症时外周痛觉信号转导和传递起到重要的作用。
OBJECTIVE: This investigation was undertaken to determine whether the sensory neuron adenosine tnphosphate receptor subunit (P2X_3 and P2Y_1) are involved in modulatory function by estrogen in the peripheral pain transduction in dorsal root ganglia. METHODS: Peripheral pain threshold test, real-time quantitative reverse transcription-polymerase chain reaction analysis, immunohistochemical methods and patch clamp recording were used to determine the mean relative concentrations of the P2X_3 and P2Y_1 receptor in rat dorsal root ganglia in Sham-OP, GDX and E_2-R rats. RESULTS: The peripheral mechanical and thermal pain threshold was decreased and increased respectively after ovariectomy in female rats, while both of them didn't alter significantly after orchiectomy in male rats. The mechanical and thermal pain threshold was increased and decreased significantly after gonadectomy with estradiol replacement. P2X_3mRNA expression was significantly increased while P2Y| mRNA expression wasdecreased after surgical ovariectomy and both were reversed after estrogen replacement. In the cultured DRG neurons, P2X_3 mRNA and P2Y_1 mRNA was significantly decreased and increased respectively 24hrs after application of 17β-estradiol in a concentration dependent manner, which was through estrogen receptors. 17β-estradiol also rapidly inhibited P2X_3 mediated transient current in DRG neurons, with PKA and PKC pathways involved. In colitis rat, P2X_3 mRNA in DRG and colon was significantly increased comparing with those from control group. While in colitis rat after ovariectomy, P2X_3 mRNA in colon but not in DRG was significantly increased comparing with that from OVX group. In DRG cells from colitis rats, 17β-estradiol modulated ATP induced inward currents. CONCLUSIONS: These results suggest that the female gonadal hormone, 17β-estradiol, might participate in control of peripheral pain signal transduction in normal and colitis rats, by modulating P2X_3 and P2Y_1 receptor-mediated events in primary sensory neurons, through non-genomic and genomic mechanisms.
引文
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