Kerekes Nóra, Mennicken Francoise, O'Donnell Dajan, Hökfelt Tomas, Hill Russell H
Karolinska Institutet, Department of Neuroscience, Retzius väg 8, SE-17177 Stockholm, Sweden.
Eur J Neurosci. 2003 Dec;18(11):2957-66. doi: 10.1111/j.1460-9568.2003.03057.x.
We examined the effect of galanin (10(-15) - 10(-7) M) on dispersed, mainly small-sized dorsal root ganglion (DRG) neurons in adult rats using whole-cell patch-clamp. Galanin and AR-M1896, a selective galanin type 2 receptor (GalR2) agonist, both significantly increased the number of action potentials in response to current pulses in 77% of the neurons, indicating an increase in excitability. Galanin also caused a rise in input resistance, decreased the holding current for -60 mV and depolarized the resting potential. In addition, Ca(2+) currents elicited by voltage steps were significantly increased by both galanin and AR-M1896 in nearly 70% of the cells. This enhancement was observed in 30% of the neurons in the presence of nimodipine or omega-conotoxin, but in each case approximately 60% less than without blocking either N- or L-type Ca(2+) channels, indicating modulation of both types of Ca(2+) channels. The percentage of small- and medium-sized neurons expressing GalR2 mRNA in DRGs in situ was similar to that showing increased excitability and Ca(2+) current after galanin application, i.e. approximately 70-80% of the neurons. The findings suggest that GalR2 has a role in controlling both the excitability, probably by inhibition of GIRK or leak K(+) channels, and Ca(2+) entry in a large population of presumably nociceptive neurons. The combination of the two effects, which possibly arise from separate biochemical pathways, would increase excitability and enhance intracellular Ca(2+) signalling which would enhance sensory transmission. These mechanisms involving GalR2 receptors may underlie the pronociceptive effects of galanin described in the literature.
我们使用全细胞膜片钳技术研究了甘丙肽（10^(-15) - 10^(-7) M）对成年大鼠分散的、主要为小型背根神经节（DRG）神经元的影响。甘丙肽和AR-M1896（一种选择性甘丙肽2型受体（GalR2）激动剂）均显著增加了77%的神经元对电流脉冲产生的动作电位数量，表明兴奋性增加。甘丙肽还导致输入电阻升高、-60 mV的钳制电流降低以及静息电位去极化。此外，在近70%的细胞中，甘丙肽和AR-M1896均使电压阶跃引发的Ca(2+)电流显著增加。在存在尼莫地平或ω-芋螺毒素的情况下，30%的神经元中观察到这种增强，但在每种情况下，比不阻断N型或L型Ca(2+)通道时减少了约60%，表明两种类型的Ca(2+)通道均受到调节。原位DRG中小、中型神经元表达GalR2 mRNA的百分比与甘丙肽作用后显示兴奋性增加和Ca(2+)电流增加的神经元百分比相似，即约70 - 80%的神经元。这些发现表明，GalR2可能通过抑制GIRK或泄漏K(+)通道来控制大量可能的伤害性神经元的兴奋性和Ca(2+)内流。这两种效应可能源于不同的生化途径，它们的组合将增加兴奋性并增强细胞内Ca(2+)信号传导，从而增强感觉传递。这些涉及GalR2受体的机制可能是文献中描述的甘丙肽促伤害感受作用的基础。
