查看Ch15.4 Sensor Transduction - Pain的源代码

本页英文内容取自：经典教材医学生理学（第三版） (Medical Physiology, 3rd Edtion, Walter F Boron, published in 2016)

中文内容由 BH1RBH (Jack Tan) 粗糙翻译

蓝色 <b style=color:#0cf>【注】</b> 后内容为 BH1RBH (Jack Tan) 所加之注释


<b style=font-size:15pt>躯体感觉受体、本体感觉和疼痛</b>

<b>SOMATIC SENSORY RECEPTORS, PROPRIOCEPTION, AND PAIN</b>

== 概述 ==

Somatic sensation is the most widespread and diverse of the body’s sensory systems (soma means “body” in Greek). Its receptors are distributed throughout the body instead of being condensed into small and specialized sensory surfaces, as most other sensory systems are arranged. Somatosensory receptors cover the skin, subcutaneous tissue, skeletal muscles, bones and joints, major internal organs, epithelia, and cardiovascular system. These receptors also vary widely in their specificity. The body has mechanoreceptors to transduce pressure, stretch, vibration, and tissue damage; thermoreceptors to gauge temperature; and chemoreceptors to sense a variety of substances. Somatic sensation (or somesthesia) is usually considered to be a combination of at least four sensory modalities: the senses of touch, temperature, body position (proprioception), and pain (nociception).

躯体感觉是身体最广泛和最多样化的感觉系统（soma 在希腊语中意为“身体”）。它的受体分布在整个身体，而不是像大多数其他感觉系统那样浓缩成小而特殊的感觉表面。体感受体覆盖皮肤、皮下组织、骨骼肌、骨骼和关节、主要内脏器官、上皮细胞和心血管系统。这些受体的特异性也差异很大。身体有机械感受器来传导压力、拉伸、振动和组织损伤;温度感受器用于测量温度;和化学感受器来感知各种物质。躯体感觉（或感觉）通常被认为是至少四种感觉模式的组合：触觉、温度、身体位置（本体感觉）和疼痛（伤害感受）。

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== 皮肤中的各种感觉末梢传导机械、热和化学刺激 ==
A variety of sensory endings in the skin transduce mechanical, thermal, and chemical stimuli

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== 皮肤中的机械感受器对特定刺激（如振动和稳定压力）敏感 ==
Mechanoreceptors in the skin provide sensitivity to specific stimuli such as vibration and steady pressure

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== 独立的温度感受器检测暖和冷 ==
Separate thermoreceptors detect warmth and cold

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== 伤害感受器是传递痛苦刺激的特殊感觉末梢 ==
Nociceptors are specialized sensory endings that transduce painful stimuli


Physical energy that is informative at low and moderate levels can be destructive at higher intensity. Sensations of pain motivate us to avoid such situations. Nociceptors are the receptors mediating acutely painful feelings to warn us that body tissue is being damaged or is at risk of being damaged (as the Latin roots imply: nocere [to hurt] + recipere [to receive]). The pain-sensing system is entirely separate from the other modalities we have discussed; it has its own peripheral receptors and a complex, dispersed, chemically unique set of central circuits. Nociceptors are free nerve endings, widely distributed throughout the body. They innervate the skin, bone, muscle, most internal organs, blood vessels, and heart. Ironically, nociceptors are generally absent from the brain substance itself, although they are in the meninges.

在低水平和中等水平下提供信息的物理能量在高强度下可能具有破坏性。痛苦的感觉促使我们避免这种情况。伤害感受器是介导剧烈痛苦情绪的受体，以警告我们身体组织正在受损或有受损的风险（正如拉丁词根所暗示的：nocere [伤害] + recipere [接收]）。疼痛感应系统与我们讨论过的其他模式完全分开;它有自己的外周受体和一组复杂、分散、化学独特的中央回路。伤害感受器是游离神经末梢，广泛分布于全身。它们支配皮肤、骨骼、肌肉、大多数内脏器官、血管和心脏。具有讽刺意味的是，尽管伤害感受器位于脑膜中，但大脑物质本身通常不存在。


Nociceptors vary in their selectivity. Mechanical nociceptors, some of which are quite selective, respond to strong pressure—in particular, pressure from sharp objects. A subset of nociceptors expresses Mas-related G protein– coupled receptor D (MrgprD); genetic ablation of just these neurons makes mice insensitive to noxious mechanical stimuli without affecting their responses to painful heat or cold. TRPA1 channels are involved in some forms of painrelated mechanosensation, and they may transduce stimuli that trigger pain originating from viscera such as the colon and bladder.

伤害感受器的选择性各不相同。机械伤害感受器，其中一些非常有选择性，对强大的压力做出反应——特别是来自尖锐物体的压力。伤害感受器的一个子集表达 Mas 相关 G 蛋白偶联受体 D (MrgprD)；仅这些神经元的基因消融使小鼠对有害的机械刺激不敏感，而不会影响它们对痛苦的热或冷的反应。TRPA1 通道参与某些形式的疼痛相关机械感觉，它们可能会转导触发源自内脏（如结肠和膀胱）的疼痛的刺激。


Thermal nociceptors signal either burning heat (above ~45°C, when tissues begin to be destroyed) or unhealthy cold; the heat-sensitive nociceptive neurons express the TRPV1 and TRPV2 channels, whereas the cold-sensitive nociceptors express TRPA1 and TRPM8 channels. A uniquely cold-resistant Na+ channel, Nav1.8, allows cold-sensitive nociceptors to continue firing action potentials even at temperatures low enough to silence other neurons.

热伤害感受器发出灼热（高于 ~45°C，当组织开始被破坏时）或不健康的寒冷的信号；热敏感伤害感受神经元表达 TRPV1 和 TRPV2 通道，而冷敏感伤害感受器表达 TRPA1 和 TRPM8 通道。独特的耐寒 Na + 通道 Nav1.8 允许对寒冷敏感的伤害感受器即使在足够低的温度下也能继续激发动作电位，使其他神经元保持沉默。


Chemical nociceptors, which are mechanically insensitive, respond to a variety of agents, including K+, extremes of pH, neuroactive substances such as histamine and bradykinin from the body itself, and various irritants from the environment. Some chemosensitive nociceptors may express TRP channels that respond to, among other things, plant-derived irritants such as capsaicin (TRPV1), menthol (TRPM8), and the pungent derivatives of mustard and garlic (TRPA1).

化学伤害感受器在机械上不敏感，对多种试剂有反应，包括 K+、极端 pH 值、来自人体本身的神经活性物质（如组胺和缓激肽）以及来自环境的各种刺激物。一些化疗敏感的伤害感受器可能表达 TRP 通道，这些通道对植物来源的刺激物有反应，例如辣椒素 （TRPV1）、薄荷醇 （TRPM8） 以及芥末和大蒜的刺激性衍生物 （TRPA1）。


Finally, polymodal nociceptors are single nerve endings that are sensitive to combinations of mechanical, thermal, and chemical stimuli. Nociceptive axons include both fast Aδ fibers and slow, unmyelinated C fibers. Aδ axons mediate sensations of sharp, intense pain; C fibers elicit more persistent feelings of dull, burning pain. The Na+ channel Nav1.7 has a particularly interesting relationship to pain. Patients with loss-of-function mutations of Nav1.7 are insensitive to noxious stimuli and experience repeated injuries because they lack protective reflexes. Several gain-of-function Nav1.7 mutations cause channel hyperexcitability and syndromes of intense chronic pain.

最后，多模式伤害感受器是对机械、热和化学刺激的组合敏感的单神经末梢。伤害性轴突包括快 Aδ 纤维和慢速无髓 C 纤维。Aδ 轴突介导剧烈疼痛的感觉;C 纤维会引起更持久的钝痛、灼痛感。Na+ 通道 Nav1.7 与疼痛的关系特别有趣。Nav1.7 功能丧失突变的患者对有害刺激不敏感，并且由于缺乏保护性反射而反复受伤。几种功能获得性 Nav1.7 突变导致通道过度兴奋和剧烈慢性疼痛综合征。


Sensations of pain can be modulated in a variety of ways. Skin, joints, or muscles that have been damaged or inflamed are unusually sensitive to further stimuli. This phenomenon is called hyperalgesia, and it can be manifested as a reduced threshold for pain, an increase in perceived intensity of painful stimuli, or spontaneous pain. Primary hyperalgesia occurs within the area of damaged tissue, but within ~20 minutes after an injury, tissues surrounding a damaged area may become supersensitive by a process called secondary hyperalgesia. Hyperalgesia seems to involve processes near peripheral receptors (Fig. 15-29) as well as mechanisms in the CNS.

疼痛的感觉可以通过多种方式进行调节。受损或发炎的皮肤、关节或肌肉对进一步的刺激异常敏感。这种现象称为痛觉过敏，它可以表现为疼痛阈值降低、感知到的疼痛刺激强度增加或自发性疼痛。原发性痛觉过敏发生在受损组织区域内，但在受伤后大约 20 分钟内，受损区域周围的组织可能会因称为继发性痛觉过敏的过程而变得超级敏感。痛觉过敏似乎涉及外周受体附近的过程 （图 15-29） 以及 CNS 中的机制。

[[文件:Physiology-ch15-29.jpg]]

Damaged skin releases a variety of chemical substances from its many cell types, blood cells, and nerve endings. These substances—sometimes called the inflammatory soup—include neurotransmitters (e.g., glutamate, serotonin, adenosine, ATP), peptides (e.g., substance P, bradykinin), various lipids (e.g., prostaglandins, endocannabinoids), proteases, neurotrophins, cytokines, and chemokines, K+, H+, and others; they trigger the set of local responses that we know as inflammation. As a result, blood vessels become more leaky and cause tissue swelling (or edema) and redness (see Box 20-1). Nearby mast cells release the chemical histamine, which directly excites nociceptors.

受损的皮肤会从其多种细胞类型、血细胞和神经末梢释放出各种化学物质。这些物质（有时称为炎症汤）包括神经递质（例如谷氨酸、血清素、腺苷、ATP）、肽（例如 P 物质、缓激肽）、各种脂质（例如前列腺素、内源性大麻素）、蛋白酶、神经营养因子、细胞因子和趋化因子、K+、H+ 等;它们触发了我们称为炎症的一组局部反应。结果，血管变得更加渗漏，并导致组织肿胀（或水肿）和发红（见方框 20-1）。附近的肥大细胞释放化学组胺，直接激发伤害感受器。


By a mechanism called the axon reflex, action potentials can propagate along nociceptive axons from the site of an injury into side branches of the same axon that innervate neighboring regions of skin. The spreading axon branches of the nociceptors themselves may release substances that sensitize nociceptive terminals and make them responsive to previously nonpainful stimuli. Such “silent” nociceptors among our small Aδ and C fibers are normally unresponsive to stimuli—even destructive ones. Only after sensitization do they become responsive to mechanical or chemical stimuli and contribute greatly to hyperalgesia. For example, the neurotrophin nerve growth factor (NGF)—part of the inflammatory soup—triggers strong hypersensitivity to heat and mechanical stimuli by modulating TRPV1 channels. Activation of TRPA1 and ASICs are also important in hyperalgesia. The cytokine tumor necrosis factor-alpha (TNF-α) potentiates the inflammatory response directly and enhances release of substances that sensitize nociceptors. Drugs that interfere with neurotrophin and cytokine actions can be effective treatments for the pain of inflammatory diseases.

通过一种称为轴突反射的机制，动作电位可以沿着伤害性轴突从受伤部位传播到同一轴突的侧支中，支配皮肤的邻近区域。伤害感受器本身展开的轴突分支可能会释放使伤害感受末梢敏感的物质，并使它们对以前无痛的刺激做出反应。在我们的小 Aδ 和 C 纤维中，这种“沉默”的伤害感受器通常对刺激没有反应——即使是破坏性的刺激。只有在致敏后，它们才会对机械或化学刺激产生反应，并极大地导致痛觉过敏。例如，神经营养因子神经生长因子 （NGF） 是炎症汤的一部分，通过调节 TRPV1 通道触发对热和机械刺激的强烈超敏反应。TRPA1 和 ASIC 的激活在痛觉过敏中也很重要。细胞因子肿瘤坏死因子-α （TNF-α） 直接增强炎症反应并增强使伤害感受器敏感的物质的释放。干扰神经营养因子和细胞因子作用的药物可以有效治疗炎症性疾病的痛苦。


The cognitive sensations of pain are under remarkably potent control by the brain, more so than other sensory system. In some cases, nociceptors may fire wildly, although perceptions of pain are absent; on the other hand, pain may be crippling although nociceptors are silent. Chronic activation of nociceptors can lead to central sensitization, a chronic enhancement of central pain-processing circuits. Prolonged activity in nociceptive axons and their spinal cord synapses causes increased glutamate release, strong activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)– and NMDA (N-methyl-D-aspartate)–type glutamate receptors, and eventually a form of long-term potentiation (see pp. 329–337).

疼痛的认知感觉受到大脑非常有效的控制，比其他感觉系统更受控制。在某些情况下，伤害感受器可能会疯狂地发射，尽管没有对疼痛的感知;另一方面，尽管伤害感受器是无声的，但疼痛可能是严重的。伤害感受器的慢性激活可导致中枢敏化，这是中枢疼痛处理回路的慢性增强。伤害性轴突及其脊髓突触的长时间活动会导致谷氨酸释放增加，AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）- 和 NMDA（N-甲基-D-天冬氨酸）型谷氨酸受体的强烈激活，并最终成为一种长期增强的形式（见第 329-337 页）。


Nonpainful sensory input and neural activity from various nuclei within the brain can modify pain. For example, pain evoked by activity in nociceptors (Aδ and C fibers) can be reduced by simultaneous activity in low-threshold mechanoreceptors (Aα and Aβ fibers). This phenomenon is a familiar experience—some of the discomfort of a burn, cut, or bruise can be relieved by gentle massage or rubbing (stimulating mechanoreceptors) around the injured area. In 1965, Melzack and Wall proposed that this phenomenon involves a circuit in the spinal cord that can “gate” the transmission of nociceptive information to the brain; control of the gate could be provided by other sensory information (e.g., tactile stimulation) or by descending control from the brain itself. Gate-like regulation of pain may arise from the modulation of gammaaminobutyric acid (GABA)–mediated and glycine-mediated inhibitory circuits in the spinal cord.

来自大脑内各种细胞核的非痛苦感觉输入和神经活动可以改变疼痛。例如，由伤害感受器（Aδ 和 C 纤维）的活动引起的疼痛可以通过低阈值机械感受器（Aα 和 Aβ 纤维）的活动来减轻。这种现象是一种熟悉的经历——一些烧伤、割伤或瘀伤的不适可以通过在受伤区域周围轻轻按摩或摩擦（刺激机械感受器）来缓解。1965 年，Melzack 和 Wall 提出，这种现象涉及脊髓中的一个回路，该回路可以“门控”伤害性信息向大脑的传输;门的控制可以由其他感觉信息（例如，触觉刺激）或通过大脑本身的下降控制来提供。疼痛的门样调节可能来自脊髓中 γ-氨基丁酸 （GABA） 介导和甘氨酸介导的抑制回路的调节。


A second mechanism for modifying the sensation of pain involves the relatively small peptides called endorphins. In the 1970s, it was discovered that a class of drugs called opioids (including morphine, heroin, and codeine) act by binding tightly and specifically to opioid receptors in the brain and, furthermore, that the brain itself manufactures “endogenous morphine-like substances,” collectively called endorphins (see p. 315).

改变疼痛感的第二种机制涉及称为内啡肽的相对较小的肽。在 1970 年代，人们发现一类称为阿片类药物（包括吗啡、海洛因和可待因）通过与大脑中的阿片受体紧密特异性结合而发挥作用，此外，大脑本身会产生“内源性吗啡样物质”，统称为内啡肽（见第 315 页）。

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== 肌梭感知骨骼肌纤维长度的变化，而高尔基肌腱器官测量肌肉的力量 ==
Muscle spindles sense changes in the length of skeletal muscle fibers, whereas Golgi tendon organs gauge the muscle’s force

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== Reference ==

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* [[Pharmacology]]
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* [[BBB]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080800/ 血脑屏障概述]

* Smith et al. Insights into inner ear function and disease through novel visualizatio of the ductus reuniens, a semila communication between hearing and balance mechanisms. JARO (2022)
* http://www.cochlea.eu/en/cochlea
* http://www.cochlea.eu/en/cochlea/cochlear-fluids

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