大鼠DRG神经元NK-1受体激活对TTX不敏感型钠通道和TRPV1受体的调制
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摘要
P物质(Substance P,SP)是速激肽家族的成员,它在神经系统中有广泛表达。在外周神经系统中,P物质主要表达在伤害性感觉神经元上,参与外周伤害性刺激信息向脊髓背角的传递。大量的研究表明,P物质的受体neurokinin-1(NK-1)在脊髓背角浅层有大量的表达,它在慢性痛的形成以及外周损伤引起的中枢敏化中发挥重要作用。
最近,越来越多的证据表明,NK-1受体除了在脊髓背角表达外,在背根节(DRG)神经元上也有表达。胞内记录和膜片钳的实验表明,SP可以引起DRG神经元和三叉神经节神经元去极化,提示DRG胞体上功能性NK-1受体的存在。免疫组织化学的证据也表明NK-1受体在支配光滑皮肤的无髓鞘纤维的轴突上有表达。我们先前的工作通过免疫组织化学和western-blot的方法直接证明了NK-1在DRG胞体上的表达。尽管如此,外周表达的NK-1受体到底有什么功能意义,还需要进一步的研究。
在DRG神经元上表达有多种钠通道,其中Na_v1.8和Na_v1.9是两种TTX不敏感型的钠通道。它们主要表达在DRG中介导伤害性信息的神经元上,在伤害性信息的处理和传递中发挥重要作用。TRPV1受体是特异性表达于伤害性感觉神经元的另一个信号分子。它是一种非选择性阳离子通道,可以被热,酸和辣椒素等多种刺激激活,是伤害性热刺激特异的换能器,在热痛觉信息传递以及病理状态引起的热痛敏中发挥重要作用。
本论文应用全细胞膜片钳,单细胞钙成像以及动物行为学测定等多种技术,研究了DRG神经元表达的NK-1受体对TTX不敏感钠通道和TRPV1受体的调制,及可其能的作用机制。结果如下:
1.Na_v1.8
在74.5%(114/153)的背根神经节小细胞上能够记录到Na_v1.8介导的高阈值激活的钠电流。给予1μM的NK-1受体激动剂[Sar~9,Met(O_2)~(11)]-substance P(Sar-SP)后,有43.3%(13/30)神经元的Na_v1.8电流显著增强。这种增强作用可以被NK-1受体特异的拮抗剂win51708以及PKC抑制剂BIM所阻断,但不能被PKA抑制剂H-89所阻断。同时,PKC亚型PKCε的抑制剂εV1-2也可以完全阻断Sar-SP的增强作用。在给予Sar-SP后,神经元动作电位阈值显著降低,而刺激诱发的动作电位发放频率则显著升高。
2.Na_v1.9
在66.1%(76/115)的DRG小细胞上可以记录到Na_v1.9电流。给予1μM的Sar-SP后,有36.0%(9/25)神经元的Na_v1.9电流显著增强。这种增强作用可以被NK-1受体特异的拮抗剂Win51708以及PKC抑制剂BIM所阻断,但不能被PKA抑制剂H-89所阻断,提示Sar-SP对Na_v1.9的调制是由PKC信号通路介导的。
3.TRPV1
在87个DRG小细胞上,有63个(72.3%)神经元可以记录到辣椒素诱导的TRPV1电流。给予1μM的Sar-SP后,有47.8%(11/23)神经元的Na_v1.9电流显著增强。Sar-SP还可以显著增强辣椒素引起的胞内钙升高以及热诱发电流,降低神经元的热反应阈值。大鼠足底皮下注射Sar-SP可以引起热痛敏反应,这种反应可以被TRPV1受体拮抗剂capsazepine所阻断,提示热痛敏是由Sar-SP对TRPV1的调制介导的。
这些结果表明,DRG神经元的NK-1受体激活后可以通过细胞内信号通路调制TTX不敏感钠通道和TRPV1受体,这可能是外周敏化的机制之一。
Substance P(SP),a member of tachykinin family,is a well-known pain-related neuropeptide in the spinal cord which is released by unmyelinated primary afferent fiber terminals of small dorsal root ganglion(DRG) neurons and participates in the spinal transmission of nociceptive signals.It is well documented that the SP receptor neurokinin-1(NK-1) is densely distributed in the superficial dorsal horn and involved in the development of chronic pain and central sensitization after intense noxious stimulation and tissue/nerve injury.
In addition to the spinal expression of the NK-1,increasing evidence strongly suggests the presynaptic expression of NK-1 in DRG neurons.The immunohistochemical evidence revealed that the NK-1 was expressed in the unmyelinated axons of the glabrous skin,and the DRG neuron soma in rats.By means of intracellular or whole-cell patch clamp recordings,SP was shown to be able to induce the depolarization of DRG or trigeminal ganglion neurons in the different species and potentiate the TRPV1 currents.However,the function of DRG-expressed NK-1 receptor needs to be further understood.
In DRG neurons,there are two types of TTX-resistant sodium channels,Na_v1.8 and Na_v1.9.They are mainly expressed in primary nociceptive neurons and play an important role in pain signal processing.TRPV1,a non-selective cation channel,is another pain-related molecular specifically expressed in nociceptors.It is activated by noxious heat,acid or capsaicin and participates in thermal pain sensation and thermal hyperalgesia.
In the present study,we investigated the modulation effects of the NK-1 agonist on Na_v1.8,Navl.9 and TRPV1 in isolated small-sized DRG neurons. 1.Na_v1.8
NK-1 agonist[Sar~9,Met(O_2)~(11)]-substance P(Sar-SP) significantly enhanced Na_v1.8 currents in a subgroup(43.3%) of DRG neurons,and the enhancement was blocked by NK-1 antagonist Win51708 and protein kinase C(PKC) inhibitor BIM,but not protein kinase A(PKA) inhibitor H-89.In particular,the inhibitor for PKCε,a PKC isoform,completely blocked this effect.Under current clamp model,Sar-SP reduced the amount of current required to evoke action potentials and increased the firing rate in a subgroup of DRG neurons.
2.Na_v1.9
Sar-SP significantly enhanced Na_v1.9 currents in 36.0%DRG neurons,and the enhancement was blocked by NK-1 antagonist Win51708 and PKC inhibitor BIM, but not protein PKA inhibitor H-89.Under current clamp model,Sar-SP significantly potentiated the spontaneous discharge of DRG neurons.
3.TRPV1
In 47.8%(11/23) TRPV1 positive DRG neurons,Sar-SP significantly enhanced capsaicin induced currents and increase in[Ca~(2+)]_i.Sar-SP also enhanced heat induced currents and reduced thermal responsive threshold.Intraplantar injection of Sar-SP caused a thermal hyperalgesia,which could be blocked by TRPV1 antagonist capsazepine.
These data suggest that activation of NK-1 receptor potentiates Na_v1.8,Na_v1.9 and TRPV1,probably participating in the generation of inflammatory hyperalgesia.
最近,越来越多的证据表明,NK-1受体除了在脊髓背角表达外,在背根节(DRG)神经元上也有表达。胞内记录和膜片钳的实验表明,SP可以引起DRG神经元和三叉神经节神经元去极化,提示DRG胞体上功能性NK-1受体的存在。免疫组织化学的证据也表明NK-1受体在支配光滑皮肤的无髓鞘纤维的轴突上有表达。我们先前的工作通过免疫组织化学和western-blot的方法直接证明了NK-1在DRG胞体上的表达。尽管如此,外周表达的NK-1受体到底有什么功能意义,还需要进一步的研究。
在DRG神经元上表达有多种钠通道,其中Na_v1.8和Na_v1.9是两种TTX不敏感型的钠通道。它们主要表达在DRG中介导伤害性信息的神经元上,在伤害性信息的处理和传递中发挥重要作用。TRPV1受体是特异性表达于伤害性感觉神经元的另一个信号分子。它是一种非选择性阳离子通道,可以被热,酸和辣椒素等多种刺激激活,是伤害性热刺激特异的换能器,在热痛觉信息传递以及病理状态引起的热痛敏中发挥重要作用。
本论文应用全细胞膜片钳,单细胞钙成像以及动物行为学测定等多种技术,研究了DRG神经元表达的NK-1受体对TTX不敏感钠通道和TRPV1受体的调制,及可其能的作用机制。结果如下:
1.Na_v1.8
在74.5%(114/153)的背根神经节小细胞上能够记录到Na_v1.8介导的高阈值激活的钠电流。给予1μM的NK-1受体激动剂[Sar~9,Met(O_2)~(11)]-substance P(Sar-SP)后,有43.3%(13/30)神经元的Na_v1.8电流显著增强。这种增强作用可以被NK-1受体特异的拮抗剂win51708以及PKC抑制剂BIM所阻断,但不能被PKA抑制剂H-89所阻断。同时,PKC亚型PKCε的抑制剂εV1-2也可以完全阻断Sar-SP的增强作用。在给予Sar-SP后,神经元动作电位阈值显著降低,而刺激诱发的动作电位发放频率则显著升高。
2.Na_v1.9
在66.1%(76/115)的DRG小细胞上可以记录到Na_v1.9电流。给予1μM的Sar-SP后,有36.0%(9/25)神经元的Na_v1.9电流显著增强。这种增强作用可以被NK-1受体特异的拮抗剂Win51708以及PKC抑制剂BIM所阻断,但不能被PKA抑制剂H-89所阻断,提示Sar-SP对Na_v1.9的调制是由PKC信号通路介导的。
3.TRPV1
在87个DRG小细胞上,有63个(72.3%)神经元可以记录到辣椒素诱导的TRPV1电流。给予1μM的Sar-SP后,有47.8%(11/23)神经元的Na_v1.9电流显著增强。Sar-SP还可以显著增强辣椒素引起的胞内钙升高以及热诱发电流,降低神经元的热反应阈值。大鼠足底皮下注射Sar-SP可以引起热痛敏反应,这种反应可以被TRPV1受体拮抗剂capsazepine所阻断,提示热痛敏是由Sar-SP对TRPV1的调制介导的。
这些结果表明,DRG神经元的NK-1受体激活后可以通过细胞内信号通路调制TTX不敏感钠通道和TRPV1受体,这可能是外周敏化的机制之一。
Substance P(SP),a member of tachykinin family,is a well-known pain-related neuropeptide in the spinal cord which is released by unmyelinated primary afferent fiber terminals of small dorsal root ganglion(DRG) neurons and participates in the spinal transmission of nociceptive signals.It is well documented that the SP receptor neurokinin-1(NK-1) is densely distributed in the superficial dorsal horn and involved in the development of chronic pain and central sensitization after intense noxious stimulation and tissue/nerve injury.
In addition to the spinal expression of the NK-1,increasing evidence strongly suggests the presynaptic expression of NK-1 in DRG neurons.The immunohistochemical evidence revealed that the NK-1 was expressed in the unmyelinated axons of the glabrous skin,and the DRG neuron soma in rats.By means of intracellular or whole-cell patch clamp recordings,SP was shown to be able to induce the depolarization of DRG or trigeminal ganglion neurons in the different species and potentiate the TRPV1 currents.However,the function of DRG-expressed NK-1 receptor needs to be further understood.
In DRG neurons,there are two types of TTX-resistant sodium channels,Na_v1.8 and Na_v1.9.They are mainly expressed in primary nociceptive neurons and play an important role in pain signal processing.TRPV1,a non-selective cation channel,is another pain-related molecular specifically expressed in nociceptors.It is activated by noxious heat,acid or capsaicin and participates in thermal pain sensation and thermal hyperalgesia.
In the present study,we investigated the modulation effects of the NK-1 agonist on Na_v1.8,Navl.9 and TRPV1 in isolated small-sized DRG neurons. 1.Na_v1.8
NK-1 agonist[Sar~9,Met(O_2)~(11)]-substance P(Sar-SP) significantly enhanced Na_v1.8 currents in a subgroup(43.3%) of DRG neurons,and the enhancement was blocked by NK-1 antagonist Win51708 and protein kinase C(PKC) inhibitor BIM,but not protein kinase A(PKA) inhibitor H-89.In particular,the inhibitor for PKCε,a PKC isoform,completely blocked this effect.Under current clamp model,Sar-SP reduced the amount of current required to evoke action potentials and increased the firing rate in a subgroup of DRG neurons.
2.Na_v1.9
Sar-SP significantly enhanced Na_v1.9 currents in 36.0%DRG neurons,and the enhancement was blocked by NK-1 antagonist Win51708 and PKC inhibitor BIM, but not protein PKA inhibitor H-89.Under current clamp model,Sar-SP significantly potentiated the spontaneous discharge of DRG neurons.
3.TRPV1
In 47.8%(11/23) TRPV1 positive DRG neurons,Sar-SP significantly enhanced capsaicin induced currents and increase in[Ca~(2+)]_i.Sar-SP also enhanced heat induced currents and reduced thermal responsive threshold.Intraplantar injection of Sar-SP caused a thermal hyperalgesia,which could be blocked by TRPV1 antagonist capsazepine.
These data suggest that activation of NK-1 receptor potentiates Na_v1.8,Na_v1.9 and TRPV1,probably participating in the generation of inflammatory hyperalgesia.
引文
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