查看Ch15.4 Sensor Transduction - Pain的源代码

== 皮肤中的机械感受器对特定刺激（如振动和稳定压力）敏感 ==
<b style=color:#0ae>Mechanoreceptors in the skin provide sensitivity to specific stimuli such as vibration and steady pressure</b>


Skin protects us from our environment by preventing evaporation of body fluids, invasion by microbes, abrasion, and damage from sunlight. However, skin also provides our most direct contact with the world. The two major types of mammalian skin are hairy and glabrous. Glabrous skin (or hairless skin) is found on the palms of our hands and fingertips and on the soles of our feet and pads of our toes (Fig. 15-26A).

皮肤通过防止体液蒸发、微生物入侵、擦伤和阳光损伤来保护我们免受环境的影响。然而，皮肤也提供了我们与世界最直接的接触。哺乳动物皮肤的两种主要类型是毛状和无毛。无毛皮肤（或无毛皮肤）存在于我们的手掌和指尖以及脚底和脚趾垫上（图 15-26A）。

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Hairy skin makes up most of the rest and differs widely in its hairiness. Both types of skin have an outer layer, the epidermis, and an inner layer, the dermis, and sensory receptors innervate both. The receptors in the skin are sensitive to many types of stimuli and respond when the skin is vibrated, pressed, pricked, or stroked, or when its hairs are bent or pulled. These are quite different kinds of mechanical energy, yet we can feel them all and easily tell them apart. Skin also has exquisite sensitivity; for example, we can reliably feel a dot only 0.006 mm high and 0.04 mm across when it is stroked across a fingertip. The standard Braille dot is 167 times higher!

毛茸茸的皮肤占其余的大部分，毛茸茸的程度差异很大。两种类型的皮肤都有外层（表皮）和内层（真皮），感觉受体支配两者。皮肤中的受体对多种类型的刺激很敏感，当皮肤受到振动、按压、刺痛或抚摸，或者皮肤毛发弯曲或拉扯时，它们会做出反应。这些是完全不同的机械能，但我们可以感觉到它们并很容易区分它们。皮肤也有精致的敏感;例如，当用指尖抚摸一个只有 0.006 毫米高和 0.04 毫米宽的点时，我们可以可靠地感觉到它。标准的盲文圆点高出 167 倍！


The sensory endings in the skin take many shapes, and most of them are named after the 19th-century European histologists who observed them and made them popular. The largest and best-studied mechanoreceptor is Pacini’s corpuscle, which is up to 2 mm long and almost 1 mm in diameter (see Fig. 15-26B). Pacini’s corpuscle is located in the subcutaneous tissue of both glabrous and hairy skin. It has an ovoid capsule with 20 to 70 onion-like, concentric layers of connective tissue and a nerve terminal in the middle. The capsule is responsible for the rapidly adapting response of the Pacini’s corpuscle. When the capsule is compressed, energy is transferred to the nerve terminal, its membrane is deformed, and mechanosensitive channels open. Current flowing through the channels generates a depolarizing receptor potential that, if large enough, causes the axon to fire an action potential (see Fig. 15-26B, left panel). However, the capsule layers are slick, with viscous fluid between them. If the stimulus pressure is maintained, the layers slip past one another and transfer the stimulus energy away so that the underlying axon terminal is no longer deformed and the receptor potential dissipates (see Fig. 15-26B, right panel). When pressure is released, the events reverse themselves and the terminal is depolarized again. In this way, the non-neural covering of Pacini’s corpuscle specializes the corpuscle for sensing of vibrations and makes it almost unresponsive to steady pressure. Pacini’s corpuscle is most sensitive to vibrations of 200 to 300 Hz, and its threshold increases dramatically below 50 Hz and above ~500 Hz. The sensation evoked by stimulation of Pacini’s corpuscle is a poorly localized humming feeling.

皮肤的感觉末梢有多种形状，其中大多数以 19 世纪的欧洲组织学家命名，他们观察了它们并使它们流行起来。最大和研究最深入的机械感受器是<b style=color:#f80>帕西尼小体 (Pacini’s corpuscle)</b>，它长达 2 毫米，直径近 1 毫米（见图 15-26B）。帕西尼小体位于无毛和多毛皮肤的皮下组织中。它有一个卵形胶囊，有 20 到 70 个洋葱状的同心结缔组织和中间的神经末梢。该囊负责帕西尼小体的快速适应反应。当胶囊被压缩时，能量被转移到神经末梢，它的膜变形，机械敏感通道打开。流经通道的电流产生去极化受体电位，如果足够大，会导致轴突触发动作电位（参见图 15-26B，左图）。然而，胶囊层很光滑，它们之间有粘性液体。如果刺激压力保持不变，各层会相互滑过并将刺激能量转移出去，这样下面的轴突末端不再变形，受体电位消散（见图 15-26B，右图）。当压力释放时，事件会自行反转，末端再次去极化。通过这种方式，帕西尼小体的非神经覆盖物使小体专门用于感知振动，使其对稳定的压力几乎没有反应。帕西尼小体对 200 到 300 Hz 的振动最敏感，其阈值在低于 50 Hz 和高于 ~500 Hz 时急剧增加。刺激 Pacini 小体所引起的感觉是一种定位不佳的嗡嗡声。


Werner Loewenstein and colleagues in the 1960s showed the importance of the Pacini corpuscle’s capsule to its frequency sensitivity. With fine microdissection, they were able to strip away the capsule from single corpuscles. They found that the resultant naked nerve terminal is much less sensitive to vibrating stimuli and much more sensitive to steady pressure. Clearly, the capsule modifies the sensitivity of the bare mechanoreceptive axon. The encapsulated Pacini corpuscle is an example of a rapidly adapting sensor, whereas the decapsulated nerve ending behaves like a slowly adapting sensor.

Werner Loewenstein 及其同事在 1960 年代证明了帕西尼小球胶囊对其频率灵敏度的重要性。通过精细的显微解剖，他们能够从单个小球上剥离胶囊。他们发现，由此产生的裸露神经末梢对振动刺激的敏感度要低得多，而对稳定的压力要敏感得多。显然，该胶囊改变了裸露机械感受轴突的敏感性。封装的帕西尼小体是快速适应传感器的一个例子，而解封的神经末梢的行为类似于缓慢适应的传感器。


Several other types of encapsulated mechanoreceptors are located in the dermis, but none has been studied as well as Pacini’s corpuscle. Meissner’s corpuscles (see Fig. 15-26A) are located in the ridges of glabrous skin and are about one tenth the size of Pacini’s corpuscles. They are rapidly adapting, although less so than Pacini’s corpuscles. Ruffini’s corpuscles resemble diminutive Pacini’s corpuscles and, like Pacini’s corpuscles, occur in the subcutaneous tissue of both hairy and glabrous skin. Their preferred stimuli might be called “fluttering” vibrations. As relatively slowly adapting receptors, they respond best to low frequencies. Merkel’s disks are also slowly adapting receptors made from a flattened, non-neural epithelial cell that synapses on a nerve terminal. They lie at the border of the dermis and epidermis of glabrous skin. It is not clear whether it is the nerve terminal or epithelial cell that is mechanosensitive. The nerve terminals of Krause’s end bulbs appear knotted. They innervate the border areas of dry skin and mucous membranes (e.g., around the lips and external genitalia) and are probably rapidly adapting mechanoreceptors.

其他几种类型的包膜机械感受器位于真皮中，但没有一种像帕西尼小体那样被研究过。<b style=color:#f80>迈斯纳小体 (Meissner’s corpuscles)</b>（见图 15-26A）位于无毛皮肤的脊上，大约是帕西尼小球的十分之一大小。它们正在迅速适应，尽管不如帕西尼小体适应。<b style=color:#f80>鲁菲尼小体 (Ruffini’s corpuscles)</b>类似于小的帕西尼小体，并且与帕西尼小体一样，出现在多毛和无毛皮肤的皮下组织中。他们喜欢的刺激可能被称为“颤动”振动。作为适应相对较慢的受体，它们对低频的反应最好。默克尔椎间盘也在缓慢适应由扁平的非神经上皮细胞制成的受体，该细胞在神经末梢上形成突触。它们位于无毛皮肤的真皮和表皮的边界。目前尚不清楚是神经末梢还是上皮细胞对机械敏感。Krause 末端球的神经末梢似乎打结了。它们支配干燥皮肤和粘膜的边界区域（例如，嘴唇和外生殖器周围），并且可能是快速适应的机械感受器。


The receptive fields of different types of skin receptors vary greatly in size. Pacini’s corpuscles have extremely broad receptive fields (Fig. 15-27A), whereas those of Meissner’s corpuscles (see Fig. 15-27B) and Merkel’s disks are very small. The last two seem to be responsible for the ability of the fingertips to make very fine tactile discriminations. Small receptive fields are an important factor in achieving high spatial resolution. Resolution varies widely, a fact easily demonstrated by measuring the skin’s two-point discrimination. Bend a paper clip into a U shape. Vary the distance between the tips and test how easily you can distinguish the touch of one tip versus two on your palm, your fingertips, your lips, your back, and your foot. To avoid bias, a colleague—rather than you—should apply the stimulus. Compare the results with standardized data (see Fig. 15-27C).

不同类型皮肤受体的感受野大小差异很大。帕西尼小球具有极宽的感受野（图 15-27A），而迈斯纳小球（见图 15-27B）和默克尔小球的感受野非常小。后两个似乎是指尖进行非常精细的触觉辨别能力的原因。小感受野是实现高空间分辨率的重要因素。分辨率差异很大，通过测量皮肤的两点区分力很容易证明这一事实。将回形针弯曲成 U 形。改变尖端之间的距离，并测试区分一个尖端和两个尖端在手掌、指尖、嘴唇、背部和脚上的触摸的难易程度。为避免偏见，应该由同事（而不是您）来实施刺激。将结果与标准化数据进行比较（参见图 15-27C）。

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The identities of somatosensory transduction molecules remain elusive. A variety of TRP channel subtypes transduce mechanical stimuli in invertebrate species (e.g., Drosophila, Caenorhabditis elegans). In mammals, rapidly adapting ion channels are associated with receptors for light touch, and several of the TRPC channels appear to be involved in sensitivity to light touch in mice. A non-TRP protein named Piezo2 is associated with rapidly adapting mechanosensory currents in mouse sensory neurons, and knocking down the expression of Piezo2 expression causes deficits in touch. Other mechanosensory channels are expressed in some sensory neurons, including TRPA1 and TRPV4, two-pore potassium channels (KCNKs), and degenerin/epithelial sodium channels (especially ASIC1 to ASIC3 and their accessory proteins), but their roles in mammalian mechanosensation are still controversial.

体感转导分子的身份仍然难以捉摸。多种 TRP 通道亚型转导无脊椎动物物种（例如，果蝇、秀丽隐杆线虫）的机械刺激。在哺乳动物中，快速适应的离子通道与轻触受体有关，并且几个 TRPC 通道似乎与小鼠对轻触的敏感性有关。一种名为 Piezo2 的非 TRP 蛋白与小鼠感觉神经元中快速适应的机械感应电流有关，敲低 Piezo2 表达会导致触觉缺陷。其他机械感觉通道在一些感觉神经元中表达，包括 TRPA1 和 TRPV4、双孔钾通道 （KCNK） 和简并蛋白/上皮钠通道（尤其是 ASIC1 至 ASIC3 及其辅助蛋白），但它们在哺乳动物机械感觉中的作用仍然存在争议。


One reason it is difficult to identify mechanosensory channels is that they often need to be associated with other cellular components in order to be sensitive to mechanical stimuli. The mechanisms by which mechanical force is transferred from cells and their membranes to mechanosensitive channels are unclear. Ion channels may be physically coupled to either extracellular structures (e.g., collagen fibers) or cytoskeletal components (e.g., actin, microtubules) that transfer energy from deformation of the cell to the gating mechanism of the channel. Mechanically gated ion channels of sensory neurons, including those requiring Piezo2, depend on the actin cytoskeleton. Some channels may be sensitive to stress, sheer, or curvature of the lipid bilayer itself and require no other types of anchoring proteins. Other channels may respond to mechanically triggered second messengers such as DAG (acting directly on the channel) or IP3 (acting indirectly via an IP3 receptor).

难以识别机械感觉通道的一个原因是，它们通常需要与其他细胞成分相关联，以便对机械刺激敏感。机械力从细胞及其膜传递到机械敏感通道的机制尚不清楚。离子通道可以物理偶联到细胞外结构（例如胶原纤维）或细胞骨架成分（例如肌动蛋白、微管），这些细胞将能量从细胞变形传递到通道的门控机制。感觉神经元的机械门控离子通道，包括需要 Piezo2 的神经元，取决于肌动蛋白细胞骨架。一些通道可能对脂质双层本身的应力、剪切或弯曲敏感，不需要其他类型的锚定蛋白。其他通道可能会响应机械触发的第二信使，例如 DAG（直接作用于通道）或 IP3（通过 IP3 受体间接作用）。


Two things determine the sensitivity of spatial discrimination in an area of skin. The first is the size of the receptors’ receptive fields—if they are small, the two tips of your paper clip are more likely to stimulate different sets of receptors. The second parameter that determines spatial discrimination is the density of the receptors in the skin. Indeed, two-point discrimination of the fingertips is better than that of the palm, even though their receptive fields are the same size. The key to finer discrimination in the fingertips is their higher density of receptors. Crowding more receptors into each square millimeter of fingertip has a second advantage: because the CNS receives more information per stimulus, it has a better chance of detecting very small stimuli.

有两件事决定了皮肤区域空间辨别的敏感度。首先是受体感受野的大小——如果它们很小，你的回形针的两个尖端更有可能刺激不同的受体组。决定空间辨别力的第二个参数是皮肤中受体的密度。事实上，指尖的两点辨别能力比手掌的两点辨别能力要好，即使它们的感受野大小相同。指尖更精细辨别的关键是它们更高密度的受体。将更多的受体塞进每平方毫米的指尖还有第二个好处：因为 CNS 每次刺激接收到更多信息，所以它有更好的机会检测到非常小的刺激。


Although we rarely think about it, hair is a sensitive part of our somatic sensory system. For some animals, hairs are a major sensory system. Rodents whisk long facial vibrissae (hairs) and feel the texture, distance, and shape of their local environment. Hairs grow from follicles embedded in the skin, and each follicle is richly innervated by free mechanoreceptive nerve endings that either wrap around it or run parallel to it. Bending of the hair causes deformation of the follicle and surrounding tissue, which stretches, bends, or flattens the nerve endings and increases or decreases their firing frequency. Various mechanoreceptors innervate hair follicles, and they may be either slowly or rapidly adapting.

虽然我们很少考虑它，但头发是我们躯体感觉系统的敏感部分。对于一些动物来说，毛发是一个主要的感觉系统。啮齿动物拂动长长的面部触须（毛发），感受当地环境的质地、距离和形状。毛发从嵌入皮肤的毛囊中长出，每个毛囊都由游离的机械感受神经末梢丰富地支配，这些神经末梢要么包裹着它，要么与它平行。头发弯曲会导致毛囊和周围组织变形，从而拉伸、弯曲或压平神经末梢，并增加或减少其放电频率。各种机械感受器支配毛囊，它们可能缓慢或迅速地适应。

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