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作者: rock_liberty 时间: 2019-5-12 09:08
0001
Section I Neurobiology of Pain
第一节 疼痛的神经生物学
Chapter 1 Peripheral Mechanisms ofCutaneous Nociception
第一章 表皮伤害性感受的外周机制
SUMMARY
摘要
Nociceptors are a specialized class of primary afferentsthat respond to intense, noxious stimuli.
伤害感受器是一种特殊类型的初级传入神经，可以对强烈的伤害性刺激做出反应。
Unmyelinated nociceptors signal the burning pain from intense heat stimuli applied to the glabrous skin of the hand, as well as the pain from sustained pressure.
无髓鞘的伤害感受器通过施加于手部无毛皮肤的强烈热刺激以及持续压力引起的疼痛来发出灼痛感。
Myelinated nociceptors signal the sharp pain from heat stimuli applied to hairy skin and from sharp mechanical stimuli.
有髓鞘的伤害感受器通过施加在多毛皮肤上的热刺激或尖锐的机械刺激来发出尖锐的疼痛信号。
Both myelinated and unmyelinated nociceptors signal pain from chemical stimuli.
有髓鞘和无髓鞘的伤害感受器均可因化学刺激而引起疼痛信号的发出。
Following a cutaneous injury, enhanced pain in response to cutaneous stimuli, called hyperalgesia, develops at the site of injury (primary hyperalgesia) and in the surrounding uninjured skin (secondary hyperalgesia).
在皮肤损伤后，在刺激皮肤时出现更强的疼痛的现象称为痛觉过敏，在原受伤部位出现时称原发性痛觉过敏，在周围未受损的皮肤出现时称继发性痛觉过敏。
Tissue injury leads to enhanced responsiveness of nociceptors, called sensitization, which accounts for primary hyperalgesia.
组织损伤导致伤害感受器的反应性增强的现象称为敏化，是原发性痛觉过敏的原因。
This sensitization is due to the local release of inammatory mediators.
这种敏化是由于炎症介质的局部释放所导致的。
Secondary hyperalgesia is due to sensitization of neurons in the central nervous system.
继发性痛觉过敏是由于中枢神经系统中神经元的敏化所致。
When nerves are severed, spontaneous activity and ectopic mechanical, thermal, and chemical sensitivity develop in the injured nociceptors.
当神经被切断时，受损的伤害感受器会出现自发活动以及异位的机械，热和化学敏感性的现象。
The properties of nearby, uninjured nociceptors are also changed.
附近未受损的伤害感受器的属性也发生了变化。
In both injured and uninjured nociceptors, responsiveness to adrenergic agents can develop, which may account for involvement of the sympathetic nervous system in certain forms of neuropathic pain.
在受损和未受损的伤害感受器中均可出现对肾上腺素能药物的反应性，这可能解释了交感神经系统在某些形式的神经病理性性疼痛中的作用。
作者: rock_liberty 时间: 2019-5-13 00:42
本帖最后由 rock_liberty 于 2019-5-13 11:00 编辑
0002
INTRODUCTION
前言
One of the vital functions of the nervous system is to provide information about the occurrence or threat of injury.
神经系统的重要功能之一是向我们提示机体受到伤害或处于被伤害的威胁中。
The sensation of pain, by its inherent aversive nature, contributes to this function.
由于其天生具有令人感到厌恶的性质，疼痛在这种功能中扮演了重要角色。
In this chapter we consider the peripheral neural apparatus that responds to noxious (injurious or potentially injurious) stimuli and thus provides a signal to alert the organism to potential injury.
在本章中，我们将讨论对有害刺激（伤害性或潜伤害性）做出反应的外周神经相关结构，正是它们发出信号来警示机体潜在伤害的存在。
Investigators have studied cutaneous sensibility by recording from single nerve fibers in different species, including humans.
研究人员通过对不同物种（含人类）的单个神经纤维进行记录来研究表皮的敏感性。
Stimuli are applied to the receptive field (i.e., area of the tissue responsive to the applied stimulus) of single fibers, and the characteristics of the neural response are noted.
我们将刺激作用于单个纤维的感受域（即对所施加的刺激进行响应的组织区域），并记录神经反应的特征。
We concentrate on the skin for three reasons.
这里有三大原因促成我们选择皮肤作为研究对象。
First, sensory receptors in the skin have been more thoroughly studied than receptors in any other tissue.
第一，与其他组织中的感受器相比，皮肤中的感受器被我们研究的更为透彻。
Second, the opportunity to perform correlative psychophysical studies in animals and humans allows powerful inferences to be made regarding function.
第二，在动物和人类中进行相关精神物理研究的机会使得对功能进行有力的推断成为了可能。（译者对这一句没有理解透彻，故以蓝色表示）
Third, cutaneous pain sensation is of great clinical significance.
第三，表皮的痛觉具有重要的临床意义。
Diseases such as post-herpetic neuralgia and others associated with small-fiber neuropathies have profound effects on cutaneous sensory function and often lead to severe pain.
诸如带状疱疹后神经痛和其他与小纤维神经病变相关的疾病对皮肤感觉功能有巨大影响，并且经常导致严重疼痛。
Highly specialized sensory fibers, alone or in concert with other specialized fibers, provide information to the central nervous system (CNS) not only about the environment but also about the state of the organism itself.
高度分化的纤维即可独立运行，亦可与其他纤维协同工作，这些高度分化的感觉纤维不仅向中枢神经系统（CNS）提供来自外部环境的信息，还向中枢神经系统提供机体本身状态的信息。
In the case of the sensory capacity of the skin, cutaneous stimuli may evoke a sense of cooling, warmth, or touch.
基于皮肤的感觉能力，施加在表皮刺激可以引发温度觉（冷或暖）或触觉。
Accordingly, certain sensory fibers are selectively sensitive to these stimuli.
相应地，特定的感觉纤维对特定的刺激敏感，具有选择性。
Warm fibers, which are predominately unmyelinated, are exclusively sensitive to gentle warming of their punctate receptive fields.
温觉纤维主要是无髓纤维，它们的点状感受域仅对温和的温暖变化敏感。
These fibers have been shown to exclusively signal the quality and intensity of the warmth sensation (Johnson et al 1979).
这些纤维已被证实只能发出温觉的质感与强度的信号(Johnson et al 1979)。
Similarly, a subpopulation of the thinly myelinated, Aδ fibers respond selectively to gentle cooling stimuli and encode the sense of cooling (Darian-Smith et al 1973).
与之类似，薄而有髓鞘的Aδ纤维亚群选择性地响应温和的冷刺激并编码冷感觉(Darian-Smith et al 1973)。
For the sense of touch, different classes of mechanoreceptive afferent fibers are exclusively sensitive to deformations of the skin.
对于触觉，不同类型的机械感觉传入纤维均仅对皮肤的形变敏感。
These lowthreshold mechanoreceptors encode such features as texture and shape.
这些低阈值机械感受器将皮肤形变的特征编码为纹理和形状。
A relatively high threshold for an adequate stimulus distinguishes the remaining class of cutaneous receptors.
一类高阈值感受器的适宜刺激将其与其他类型的表皮感受器区分开来。
Because these receptors respond preferentially to noxious stimuli, they are termed nociceptors (Sherrington 1906).
因为这些受体优先响应有害刺激，所以它们被称为伤害感受器(Sherrington 1906)。
Among the many varieties of sensory receptors, nociceptors are distinctive in that they typically respond to the multiple energy forms that produce injury (thermal, mechanical, and chemical stimuli) and provide information to the CNS regarding the location and intensity of noxious stimuli.
在各种感受器中，伤害感受器的独特之处在于它们通常响应造成损伤的多种能量形式（热，机械和化学刺激），并向中枢神经系统提供关于有害刺激的位置和强度的信息。
Nociceptors may be subclassified with respect to four criteria: (1) unmyelinated C-fiber afferents (conduction velocity <2 m/sec) versus myelinated A-fiber afferents (conduction velocity >2 m/sec), (2) modalities of stimulation that evoke a response, (3) response characteristics, and (4) distinctive chemical markers (e.g., receptors expressed on the membrane).
伤害感受器可以依据四个标准进行分类：
- 无髓鞘C-传入纤维（传导速度<2米/秒）与有髓A-传入纤维（传导速度> 2米/秒）
- 刺激的能量形式
- 反应的特点
- 独特的化学标记物（例如，在膜上表达的受体）。
We first consider the properties of cutaneous nociceptors and then review how their function is thought to relate to the sensation of pain.
我们首先讨论表皮伤害感受器的特性，然后回顾它们的功能是如何被认为与疼痛的感觉有关的。
Tissue damage results in a cascade of events that lead to enhanced pain in response to natural stimuli, termed hyperalgesia.
组织损伤导致一系列事件，这些事件使得原有刺激所引发的疼痛增强的现象，称为痛觉过敏。
A corresponding increase in the responsiveness of nociceptors, called sensitization, occurs.
伤害感受器的响应性的出现相应的增加的现象，称为敏化。
The characteristics of hyperalgesia and its neurophysiological counterpart sensitization are discussed in a later section.
痛觉过敏的特征及其神经生理学对应敏化作用将在后面的章节中讨论。
Finally, we consider how nociceptors may play a role in accounting for the often severe pain that accompanies nervous system injury and disease.
最后，我们讨论伤害感受器如何在解释神经系统损伤和疾病伴随的严重疼痛中发挥作用。
作者: rock_liberty 时间: 2019-5-13 00:46
本帖最后由 rock_liberty 于 2019-5-14 17:33 编辑
0003
PROPERTIES OF NOCICEPTORS IN UNINJURED SKIN
未受损伤皮肤中伤害感受器的特点
Nature might have designed nociceptors such that each had the capacity to respond to the full complement of stimulus energy forms that pose potential risks to the organism (thermal, mechanical, and chemical).
伤害感受器也许是天工造物，它们使得每个人都具备了应对潜在的伤害性刺激能量（热能、机械能与化学能）的能力。
What nature has adopted instead is a mixed strategy whereby many nociceptors respond to multiple stimulus modalities (polymodal) and others have more specialized response properties.
大自然所创造的伤害感受器大多都采取了一种复合策略，即它们可以响应多种刺激能量，而其他类型的感受器所响应的刺激能量大多较为专一。
These specialized response properties probably at least in part account for different aspects of nociceptive sensory function (e.g., burning, aching, pricking, prickle, itch).
其他类型的感受器的这些专一化的响应特性可能至少部分地参与了伤害性感觉功能的各种方面（例如，灼烧感，隐痛，针刺感，刺痛，瘙痒）。
As delineated later, nociceptors have distal effector functions as well, and specialization may also play a role here.
如后所述，伤害感受器也有远端效应器功能，专一化也可能在这里发挥作用。
The end result is that nociceptors have a complex biology and heterogeneous properties.
最终呈现给我们的结果是，伤害感受器具有复杂的生物学特性和异质性。
The receptive field of a nociceptor is often first localized by use of mechanical stimuli.
伤害感受器的感受域通常首先通过机械刺激进行定位。
Various other stimulus modalities are then applied to this receptive field.
然后将各种其他刺激方式也施加于该感受域。
In most early studies of nociceptors, only heat and mechanical stimuli were used to study nociceptors.
在大多数伤害性感受器的早期研究中，仅使用了热和机械刺激来进行研究。
Therefore, the nomenclature of CMH and AMH is often used to refer to C-fiber mechano-heat–sensitive nociceptors and A-fiber mechano-heat–sensitive nociceptors, respectively.
因此，CMH和AMH的命名通常分别用于指C-纤维机械-热敏感伤害感受器和A-纤维机械-热敏感伤害感受器。
If a fiber responds to heat and mechanical stimuli, the fiber will in most cases respond to chemical stimuli as well (Davis et al 1993b).
如果一种纤维对热和机械刺激作出反应，它在大多数情况下也会对化学刺激产生反应 (Davis et al 1993b)。
Thus, CMHs and AMHs may also be referred to as polymodal nociceptors.
因此，CMH和AMH也可称为多模式伤害感受器。
The issue of whether a given nociceptor responds to a particular stimulus modality is perilous because the presumed lack of response to a given modality may in fact represent failure to apply the stimulus with sufficient intensity.
判断特定伤害感受器是否对特定刺激方式做出响应的问题是很艰难的，因为对给定刺激方式而缺乏响应的这种假设实际上可能是因为刺激的强度不够。
The problem with the application of high-intensity stimuli is that the stimulus may alter the properties of the nociceptor in an enduring manner.
对于施加高强度刺激的问题，其症结在于，刺激可以长久地改变伤害感受器的性质。
A selection bias occurs: nociceptors with lower thresholds are more likely to be studied.
这就会出现选择偏倚：具有较低阈值的伤害感受器更有可能被我们研究到。
The easiest way to find a nociceptor for electrophysiological study is to apply squeezing (mechanical) stimuli to the skin and thus identify the receptive field.
用电生理学研究的方法找到伤害感受器的最简单办法是对皮肤施加挤压（机械）刺激，从而识别感受域。
This selection process identifies what are termed mechanically sensitive afferents (MSAs).
该选择过程是在辨识所谓的机械敏感传入(MSAs)。
In time it has become apparent that selection bias from this approach has led to oversight of an important class of nociceptors: mechanically insensitive afferents (MIAs).
随着时间的推移，显然这种方法的选择偏差导致了对一类重要的伤害感受器的忽视：机械不敏感的传入(MIAs)。
Because these fibers by definition have high mechanical thresholds (or are unresponsive to mechanical stimuli), finding the mechanical receptive field of these fibers is difficult.
因为根据定义，这些纤维具有高机械阈值（或对机械刺激没有反应），所以发现这些纤维的机械感受域是困难的。
An alternative technique described by Meyer and colleagues (1991) has been to apply electrical stimuli to the skin to identify the putative receptive field.
Meyer及其同事（1991）描述的另一种技术是将电刺激应用于皮肤以识别假定的感受域。
With this technique it turns out that about half of the Aδ-fiber nociceptors and 30% of the C-fiber nociceptors are MIAs, with MIAs being defined as afferents that have very high mechanical thresholds (>6 bar = 600 kPa = 60 g/mm2) or are unresponsive to mechanical stimuli (Handwerker et al 1991, Meyer et al 1991).
通过这种技术，我们发现大约一半的Aδ纤维伤害感受器和30％的C纤维伤害感受器都是MIA，MIA被定义为具有很高机械阈值的传入（> 6 bar = 600 kPa = 60 g / mm2）或对机械刺激无反应(Handwerker et al 1991, Meyer et al 1991)。
MIAs have also been reported in the knee joint (Schaible and Schmidt 1985), viscera (Häbler et al 1988), and cornea (Tanelian 1991).
在膝关节（Schaible和Schmidt 1985），内脏（Häbler等1988）和角膜中（Tanelian 1991）也报道了MIA。
As will be seen, this MIA–MSA distinction is of significance with regard to distinguishing nociceptor types.
可以看出，这种MIA-MSA区别在区分伤害感受器类型方面具有重要意义。
From the perspective of nomenclature, it is well to emphasize that MIAs are not defined as fibers that have no response to mechanical stimuli but rather as fibers that have a very high threshold (or no sensitivity at all) such that demonstration of a response to mechanical stimuli in electrophysiological studies is difficult.
从命名的角度来看，强调MIAs不是对机械刺激没有反应的纤维，而是具有非常高的阈值（或根本没有灵敏度）的纤维具有重要意义，证实了在电生理学研究中，判断特定伤害感受器是否对特定刺激方式做出响应的问题是很艰难的。
作者: rock_liberty 时间: 2019-5-13 00:47
本帖最后由 rock_liberty 于 2019-5-21 02:20 编辑
0004
C-Fiber Nociceptors
C纤维伤害感受器
CMHs are commonly encountered cutaneous afferents, and activity of sufficient magnitude in these fibers is thought to evoke a burning pain sensation.
C纤维-机械-热-敏感伤害感受器（CMHs）通常与皮肤的传入纤维相交汇，当这些纤维的活动强度达到足够的大小时，我们认为是其引起了灼痛的感觉。
The size of the receptive field appears to scale with the size of the animal.
感受域的大小似乎与动物的体积成比例。
Typical values for monkey are between 15 and 20 mm2 (LaMotte and Campbell 1978), and for human they are near 100 mm2 (Schmidt et al 1997).
猴子感受域的典型范围在15到20平方毫米之间（LaMotte和Campbell 1978），而对于人类，它们接近100平方毫米（Schmidt等1997）。
There are often discrete areas of mechanical sensitivity (hot spots) within the receptive field, but in many fibers the areas of mechanical responsiveness tend to fuse over the region of the receptive field.
在感受域内通常存在离散的机械敏感区域（热点），但在许多纤维的感受域中，机械响应区域倾向于融为一体。
Most CMHs respond to chemical stimuli (though not as well as A-fiber nociceptors; Davis et al 1993b) and can therefore be considered polymodal.
大多数CMH对化学刺激有反应（虽然不如A纤维伤害感受器; Davis等1993b），因此可以被认为具有多模式。
Responses to heat stimuli have been studied in considerable detail.
我们已经将对热刺激的响应进行了详尽的研究。
Figure 1-1. Responses of a typical C-fiber nociceptor and a warm fiber to heat stimuli. Heat stimuli ranging from 41-49°C and lasting 3 seconds were presented at 25-second interstimulus intervals to the glabrous skin of the monkey hand. Each stimulus occurred with equal frequency and was preceded by every other stimulus an equal number of times. Within these constraints, the order of stimulus presentation was randomized. Base temperature between stimuli was 38°C. A, Monotonic stimulus–response function for a typical nociceptor. B, Non-monotonic stimulus–response function for a typical warm fiber. The solid line represents the total response to a given temperature averaged across all presentations. The dotted lines represent the stimulus–response functions obtained when the preceding temperature was of low (41 and 43°C) or high (47 and 49°C) intensity. (Reproduced with permission from LaMotte RH, Campbell JN 1978 Comparison of responses in warm and nociceptive C-fiber afferents in monkey with human judgements of thermal pain. Journal of Neurophysiology 41:509–528.)
Figure 1-1. 典型的C纤维伤害感受器和温热纤维对热刺激的反应。 对猴子手部的无毛皮肤施加范围为41~49°C的热刺，持续3秒，每次刺激间隔25秒。 每一刺激的频率均一致，并且在每个其他刺激之前发生相同的次数。 在这些条件的约束下，刺激施加的顺序是随机的。 基础环境温度为38℃。 A，典型伤害感受器的单调刺激 - 反应曲线。 B，典型温暖纤维的非单调刺激 - 响应曲线。 实线表在所有给定温度的平均值下的总反应情况。 虚线表示当前一刺激的温度为低（41和43°C）或高（47和49°C）强度时获得的刺激响应曲线。(Reproduced with permission from LaMotte RH, Campbell JN 1978 Comparison of responses in warm and nociceptive C-fiber afferents in monkey with human judgements of thermal pain. Journal of Neurophysiology 41:509–528.)
The response of a typical CMH to a random sequence of heat stimuli ranging from 41–49°C is shown in Figure 1-1A.
典型的CMH对41-49°C范围内随机序列热刺激的响应如Figure 1-1A所示。
It can be seen that the response increases monotonically with stimulus intensity over this temperature range, which encompasses the pain threshold in humans.
可以看出，在该温度范围内，响应随着刺激强度单调增加，人类的疼痛阈值亦包含在其中。
One ion channel involved in the transduction of heat at nerve terminals is thought to be the neuronal transient receptor potential ion channel V1 (TRPV1); activity in this channel increases with increasing temperature (Caterina et al 1997).
一种参与神经末梢热传导的离子通道被命名为神经元瞬时受体电位离子通道V1（TRPV1）; 该通道中的活性随着温度的升高而增加（Caterina等1997）。
A detailed description of the neuronal ion channels involved in stimulus transduction is presented in Chapter 2 (for review see Dubin and Papapoutian 2010).
有关刺激转导的神经元离子通道的详细描述见第2章（综述见Dubin和Papapoutian 2010）。
Figure 1-4. Schematic illustration of unmyelinated fiber terminations in the epidermis. Non-peptidergic, MrgD+ neurons terminate as free nerve endings in the most superficial layers of the epidermis. Peptidergic neurons terminate in deep layers of the epidermis. Some of the signaling receptors found on keratinocytes and free nerve endings are also illustrated. (Artwork by Ian Suk, Johns Hopkins University; adapted from Dussor G, Koerber HR, Oaklander AL, et al 2009 Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Research Reviews 60:24–35.)
Figure 1-4. 表皮中无髓鞘纤维末梢的示意图。非肽类，MrgD(+)的神经元以游离神经末梢的形式终止于表皮的最浅层。肽能神经元终止于表皮的深层。在角质层上发现的一些信号传导手提以及游离神经末梢亦在示意图中表示了出来。(Artwork by Ian Suk, Johns Hopkins University; adapted from Dussor G, Koerber HR, Oaklander AL, et al 2009 Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Research Reviews 60:24–35.)
Signal transduction molecules on keratinocytes may also play a role in heat transduction by inducing the release of adenosine triphosphate (ATP), which activates purinergic receptors (P2X3 and P2Y2) on the free nerve endings (see Fig. 1-4).
角质形成细胞上的信号转导分子也可通过诱导三磷酸腺苷（ATP）的释放而在热转导中起作用，其激活游离神经末梢上的嘌呤能受体（P2X3和P2Y2）(see Fig. 1-4).
Two types of heat response are observed following a stepped heat stimulus.
在阶梯式热刺激之后观察到两种类型的热响应。
Figure 1-2. Two types of heat responses are observed in C-fiber nociceptors. A, Stepped heat stimulus (49°C, 3 seconds) used to classify heat response. B, The quick C (QC) fiber (yellow circles) exhibits a high-frequency discharge during the rising phase of the stimulus that adapts quickly (within 1 second). The slow C (SC) fiber (blue circles) exhibits a relatively uniform discharge throughout the stimulus period. Each circle represents the time of occurrence of an action potential. C, A histogram of the heat thresholds reveals that the distributions of QC and SC fibers are almost non-overlapping. (From Johanek LM, Meyer RA, Friedman RM, et al 2008 A role for polymodal C-fiber afferents in nonhistaminergic itch. Journal of Neuroscience 28:7659–7669.)
Figure 1-2.在C纤维伤害感受器中观察到两种类型的热响应。 A，阶梯式热刺激（49°C，3秒）用于对热响应分类。 B，快速C（QC）纤维是快适应型感受器（在1S内适应），在刺激的上升阶段表现出高频放电（黄色圆圈）。 缓慢的C（SC）纤维，在整个刺激期间表现出相对均匀的放电（蓝色圆圈）。 每个圆圈表示动作电位发生的时间。 C，热阈值的直方图显示QC和SC纤维的分布几乎不重叠。(From Johanek LM, Meyer RA, Friedman RM, et al 2008 A role for polymodal C-fiber afferents in nonhistaminergic itch. Journal of Neuroscience 28:7659–7669.)
Quick C (QC) fibers exhibit their peak discharge during the rising phase of the heat stimulus, whereas slow C (SC) fibers exhibit their peak discharge during the plateau phase (Fig. 1-2B).
快速C（QC）纤维的放电峰在热刺激的上升阶段出现，而缓慢的C（SC）纤维的放电峰在平台阶段表现出峰值放电(Fig. 1-2B)。
The heat thresholds (Fig. 1-2C) and mechanical thresholds of QC fibers are significantly lower than those of SC fibers, thus suggesting that they may be located more superficially in the epidermis.
QC纤维的热阈值(Fig. 1-2C)和机械阈值显着低于SC纤维的阈值，因此表明它们在表皮中的位置更加表浅。
QC fibers respond more vigorously to pruritic stimuli than do SC fibers, which suggests that they may be important in itch sensations (Johanek et al 2008).
QC纤维对瘙痒刺激的反应比SC纤维更强烈，这表明它们在瘙痒感觉中可能具有重要作用(Johanek et al 2008)。
Thermal modeling studies combined with electrophysiological analysis have indicated that (1) the heat threshold of CMHs depends on the temperature at the depth of the receptor and not the rate of increase in temperature, (2) transduction of heat stimuli (conversion of heat energy to action potentials) occurs at different skin depths for different CMHs (Tillman et al 1995b), and (3) suprathreshold responses of CMHs vary directly with the rate of increase in temperature (Tillman et al 1995a, 1995b; Yarnitsky et al 1992).
热调节研究结合电生理学分析表明：
CMHs的热阈值取决于受体所处深度处的温度，而不是温度升高的速率
对于不同的CMH，热刺激的转换（热能转换为动作电位）发生在不同的皮肤深度(Tillman et al 1995b)
CMH的超阈值响应直接随温度的升高速率而变化(Tillman et al 1995a, 1995b; Yarnitsky et al 1992)
The depth of the heat-responsive terminals of CMHs varies quite widely (ranging from 20–570 μm; Tillman et al 1995b).
CMH的热响应末梢的深度变化相当广泛（范围为20-570μm; Tillman et al 1995b）。
When a stepped temperature stimulus is applied to the skin, the temperature increases in the subsurface levels more slowly because of thermal inertia.
当对皮肤施加阶梯式温度刺激时，由于热惯性，温度在深处上升得更慢。
The disparity in the surface temperature and the temperature at the level of the receptor varies directly with depth and indirectly with time.
皮肤表面温度和受体水平温度的差异直接随深度而变化，间接随时间变化。
Given that the depth of CMH terminals varies widely, true heat thresholds are obtained when the rate of increase in temperature is very gradual or when the duration of the stimulus is very long.
鉴于CMH末梢的深度变化很大，当温度增加速率非常缓慢或刺激持续时间很长时，才能获得真正的热阈值。
Although the literature reflects a wide range of heat thresholds for CMHs, when tested with these types of heat stimuli, the heat threshold of the majority of CMHs is in a remarkably narrow range of 39–41°C (Tillman et al 1995b).
尽管文献描述了CMH的各种热阈值，在用这些类型的热刺激进行测试时，大多数CMH的热阈值在39-41°C这一非常窄的范围内（Tillman等1995b）。
The response of CMHs is also strongly influenced by the stimulus history.
CMH的反应也受到过去的刺激的的强烈影响。
Both fatigue and sensitization are observed.
敏化与疲劳的现象均可被观察到。
One example of fatigue is the observation that the response to the second of two identical heat stimuli is substantially less than the response to the first stimulus.
举例说明所观察到的疲劳现象，我们观察到，对于两个相同热刺激，对第二个热刺激的响应明显小于对第一个热刺激的响应。
This fatigue is dependent on the time between stimuli, with full recovery taking longer than 10 minutes.
这种疲劳的程度取决于刺激之间的时间间隔，完全恢复需要超过10分钟。
A similar reduction in the intensity of pain after repeated heat stimuli is observed in human subjects (LaMotte and Campbell 1978).
在人类受试者中能观察到，在反复热刺激后疼痛强度存在类似的降低（LaMotte和Campbell 1978）。
Fatigue is also apparent in Figure 1-1A, where the response to a given stimulus varied inversely with the intensity of the preceding stimulus.
疲劳现象在Figure 1-1A中也很明显，如果将两次刺激的响应情况进行对比，第二次刺激对应的响应的强度与第一次刺激的强度成反比。
A decrease in the response to heat is also observed following mechanical stimuli applied to the receptive field or electrical stimuli applied to the nerve trunk (Peng et al 2003).
对感受域施加机械刺激对神经干施加电刺激后，也能观察到对热刺激的响应强度降低（Peng等，2003）。
This suggests that fatigue in response to a given stimulus modality can be induced by heterologous stimulation, that is, by excitation with a stimulus of a different modality.
这就表明，通过异源刺激可以诱导出给定刺激类型所对应的响应的疲劳现象，即通过不同类型的刺激均可引发。
Interestingly, recovery from cross-modal or heterologous fatigue is faster than recovery from fatigue induced by a stimulus of the same modality.
有趣的是，相较于相同类型刺激下所引发的疲劳现象，不同刺激类型（异源刺激）引发的疲劳现象所需的恢复时间更短。
Presumably, this is because these heterologous stimuli do not activate and therefore do not fatigue the stimulus transduction apparatus in the same way.
我们推测，这是因为异源刺激是以不同的方式激活传导通路的，因而所引发的疲劳现象也有所不同。
Alternatively, fatigue may arise from independent effects on spike initiation (from antidromic stimulation) and transduction (from natural stimulation at the receptive field).
亦这种可能性：疲劳现象可能是形成动作电位（来自逆向刺激）和转导（来自感受域的自然刺激）的独立影响所引发的。
Fatigue in response to heat stimuli is also seen in vitro when small (and presumably nociceptive) dorsal root ganglion (DRG) cells are repetitively tested with heat stimuli (Greffrath et al 2002).
当在体外用热刺激重复测试小的（并且可能是伤害性的）背根神经节（DRG）细胞时，也可观察到对热刺激的响应疲劳现象（Greffrath等2002）。
The enhanced response, or sensitization, that may occur in CMHs after tissue injury is described below in the section on hyperalgesia.
组织损伤后可能在CMH中发生的敏化将在下文的痛觉过敏部分中描述。
Responses to mechanical stimuli are covered in more detail later.
对机械刺激的响应的细节将在后文中进行介绍。
Suffice it here to indicate that CMHs usually display a slowly adapting response to mechanical stimuli of a given force.
这里需要指出的是，在给定力的机械刺激下，CMH通常是慢适应的。
As noted later, MSA CMHs have a graded response to punctate stimuli, but their stimulus–response functions become saturated at levels substantially below the threshold for pain.
如后所述，MSA（机械敏感传入神经） CMH对点状刺激有分级反应，但其刺激-反应曲线在低于疼痛阈值的水平上变得饱和。
C-fiber MIAs are heterogeneous with regard to responses to chemical and heat stimuli, and some respond only to mechanical stimuli (but of course with a very high mechanical threshold).
C纤维MIA（机械不敏感传入神经）在对化学和热刺激的反应方面是异质的，并且它们中的一些仅响应机械刺激（但机械阈值非常高）。
The sensitivity to mechanical stimuli has no obvious correlation to the heat threshold (Davis et al 1993b).
对机械刺激的敏感性与热阈值之间不存在明显的相关性（Davis等，1993b）。
In contrast to CMH afferents, some C-fiber MIAs in humans are vigorously excited when challenged with histamine or capsaicin.
与CMH传入相反，使用组胺或辣椒素可强烈兴奋人类的一些C纤维MIA。
In addition, the activity observed in these C-fiber MIAs parallels the duration of the perception of itch (histamine) or burning pain (capsaicin) (Schmelz et al 1997, 2000b).
此外，在这些C纤维MIA中观察到的兴奋状态与瘙痒（组胺）或灼痛（辣椒素）感知的持续时间相似（Schmelz等1997,2000b）。
C-fiber MIAs may therefore act as chemosensors.
因此，C纤维MIA可以被视为化学感受器。
In addition to pronounced chemosensitivity, these fibers have some other interesting properties that could account for pain in response to tonic pressure stimuli or the neurogenic flare response (see below).
除了显著的的化学敏感性外，这些纤维还具有一些其他有趣的特性，可以对强直性压力刺激或神经源性反应所引起的疼痛进行解释（见下文）。
Low-threshold C-fiber mechanoreceptors that do not re- spond to heat have been described in the cat (Bessou and Perl 1969) and rabbit (Shea and Perl 1985).
在猫（Bessou和Perl 1969）和兔子（Shea和Perl 1985）中，他们描述了不对热的低阈值C-纤维机械感受器。
In primates, including humans, these fibers have been found in proximal areas of the body (Kumazawa and Perl 1977, Nordin 1990) and the hairy skin on the forearm (Vallbo et al 1999).
在包括人类在内的灵长类动物中，我们已经在身体的近端区域（Kumazawa和Perl 1977，Nordin 1990）和前臂上的多毛皮肤（Vallbo等1999）发现了这些纤维。
These afferents are strongly activated by innocuous mechanical stimuli moved slowly across the receptive field, but they also respond to pinprick stimuli.
这些传入神经被在感受域上缓慢移动的无害的机械刺激强烈激活，但它们也对针刺刺激作出反应。
The neuronal activity in these fibers is not critical for the perception of touch and, according to one imaging study, leads to the activation of the insular but not the sensory cortex (Olausson et al 2003).
这些纤维引起的神经元活动对于触觉的感知并不重要，并且根据一项影像学研究，它们引起脑岛而非感觉皮层的激活（Olausson等人2003）。
Low-threshold C-fiber mechanoreceptors are thought to mediate the sensation of “pleasant” touch and may therefore play an important role in “affiliative” behavior (Vallbo et al 1999, Wessberg et al 2003, Löken et al 2009).
低阈值C-纤维机械感受器被认为介导“愉快”触觉的感觉，因此可能在“亲近”行为中起重要作用（Vallbo等1999，Wessberg等2003，Löken等2009）。
Some mechano-insensitive C fibers are reported to be activated by non-noxious and noxious cold and hot stimuli.
据报道，一些对机械不敏感的C纤维能偶被非有害和有害的冷热刺激所激活。
It has been hypothesized that activity in these afferents may mediate the “hot–burning” sensations caused by such stimuli.
已有假说认为，这些传入神经的活动可以介导由这些刺激引起的“热-燃烧”感觉。
These afferents may also be involved in mediating psychophysical
phenomena such as “paradoxical heat” or the thermal grill illusion (Campero et al 2009).
这些传入神经也可能参与介导精神物理现象，如“矛盾热”或热烧烤错觉（Campero等2009）。
C-fiber afferents differ not only in their receptive features but also in their conductive properties.
不仅在作为感受器的方面的特点，C纤维传入神经在传导方面也有与众不同的特点。
In fact, their conductive and receptive properties appear to correlate.
事实上，它们的作为感受器的方面的特点和传导方面的特点似乎具有相关性。
When unmyelinated C-fiber afferents are activated repetitively by electrical stimuli, their conduction latency increases gradually (i.e., the conduction velocity of the afferent decreases).
当通过电刺激重复激活无髓鞘的C纤维传入神经时，它们的传导潜伏期逐渐增加（即传入纤维的传导速度减小）。
In addition, with increasing stimulation frequency, the amount of this activity-dependent slowing increases.
此外，随着刺激频率的增加，这种依赖于兴奋状态的减速的量同时增加。
Slowing in C-fiber MIAs is greater than in C-fiber MSAs (Weidner et al 1999), and mechanosensitive nociceptive afferents show more pronounced slowing than do cold-sensitive C fibers, low-threshold C fibers, or sympathetic efferent C fibers (Gee et al 1996, Serra et al 1999, Obreja et al 2010, Ringkamp et al 2010).
C纤维MIAs比C纤维MSA的减速现象更显著（Weidner等1999），机械敏感性伤害性传入神经表现出比冷敏感C纤维，低阈值C纤维或交感神经传出C纤维更明显的减速现象（Gee等1996，Serra等1999，Obreja等2010，Ringkamp等2010）。
This difference in slowing properties indicates that the ion channels responsible for conduction may be different and suggests that the ion channels responsible for spike initiation at the receptive terminal may also differ between C-fiber classes.
这种减速现象的差异表明，负责传导的离子通道可能有所不同，并且提示我们，在感受末梢处负责形成动作电位的离子通道在不同C纤维类别之间也可能有所不同。
作者: tianxialonggang 时间: 2019-5-13 12:47
本帖最后由 tianxialonggang 于 2019-5-13 12:53 编辑
谢谢分享！
作者: rock_liberty 时间: 2019-5-30 13:18
最近参加考试，考试结束恢复更新！！
作者: rock_liberty 时间: 2019-6-16 19:22
0005
A-FiberNociceptors
A纤维伤害感受器
A-fiber nociceptors are thought to evoke pricking pain, sharpness, and perhaps aching pain.
A纤维伤害感受器被认为会引起刺痛，尖锐，可能引起酸痛。
As a general rule, A-fiber nociceptors do what C-fiber nociceptors do, but do it more robustly.
一般情况下，A纤维伤害感受器与C纤维伤害感受器的功能类似，但更强劲。
They respond at higher discharge frequencies, and the discriminable information supplied to the CNS is greater (e.g., Slugg et al 2000).
它们相迎的放电频率更高，并且提供给CNS的可辨别信息更充实 (e.g., Slugg et al 2000)。
Two types of A-fiber nociceptors are apparent (Dubner et al 1977, Treede et al 1998).
两种类型的A纤维伤害感受器可谓是泾渭分明（Dubner等1977，Treede等1998）。
A summary of their properties is presented in Table 1-1.
Table 1-1展示了它们各自的性质。
Type I fibers are typically responsive to heat, mechanical, and chemical stimuli and may therefore be referred to as AMHs or polymodal nociceptors.
I型纤维通常对热，机械和化学刺激有反应，可称为AMH或多模式伤害感受器。
Because the heat thresholds are high with short-duration stimuli (typically >53°C), the responsiveness of these fibers to heat has in some studies been overlooked.
由于在短时间刺激下，其热阈值很高（通常> 53°C），因此在一些研究中忽略了这些纤维的反应性。
Consequently, these fibers have been called high-threshold mechanoreceptors (HTMs) by many investigators (e.g., Burgess and Perl 1967).
因此，许多研究人员称这些纤维称为高阈值机械感受器（HTM）（例如，Burgess和Perl 1967）。
Heat sensitivity in type I fibers is most likely mediated by the vanilloid receptor–like protein 1 (VRL1, renamed TRPV2) since it has a similar high threshold for activation by heat and is expressed in neurons with small myelinated axons (Caterina et al 1999).
I型纤维的热敏感性很可能是由辣椒素受体样蛋白1（VRL1，已更名为TRPV2）介导的，因为其具有类似的热激活的高阈值，并且在小髓鞘轴突上表达(Caterina et al 1999)。
When heat thresholds are determined with longduration temperature stimuli, however, thresholds are in the mid-40–50°C range (Treede et al 1998).
然而，当用长时间温度刺激来明确其热阈值时，该值在40-50℃的之间范围内（Treede等1998）。
Type I AMHs are seen in hairy and glabrous skin (Campbell et al 1979) and have also been described in the cat and rabbit (Fitzgerald and Lynn 1977, Roberts and Elardo 1985).
I型AMH见于多毛和无毛的皮肤（Campbell等1979），并且在猫和兔中也有描述（Fitzgerald和Lynn 1977，Roberts和Elardo 1985）。
The mean conduction velocity of type I AMHs in the monkey is 25 m/sec and extends as high as 55 m/sec.
猴子中I型AMH的平均传导速度为25米/秒，并可提高至达55米/秒。
Thus, by conduction velocity criteria, type I AMHs fall into a category between that of Aδ and Aβ fibers.
因此，通过传导速度标准界定，I型AMH属于Aδ和Aβ之间的类别。
Nearly all type I AMHs are MSAs.
几乎所有I型AMH都是MSA（机械敏感传入纤维）。
Their receptive field size is similar to that of CMHs, but the presence of “hot spots” in response to mechanical stimuli is much more obvious.
它们的感受域大小与CMH类似，但是响应机械刺激的“热点”的存在更为明显。
Type II A-fiber nociceptors were encountered only infrequently in early studies.
II型A纤维伤害感受器仅能在早期研究中见到。
It turns out that this is because the thresholds to mechanical stimuli place the majority of these fibers in the MIA category.
事实表明，这是因为机械刺激的阈值将大多数这些纤维置于MIA（机械不敏感传入纤维）类别中。
Many have no demonstrable response to mechanical stimuli.
许多人对机械刺激没有明显的反应。
When an unbiased electrical search stimulus is used, however, the prevalence of type I and type II A-fiber nociceptors in the hairy skin of the primate is similar.
然而，当使用无偏的电搜索刺激时，灵长类动物的毛皮中I型和II型A型纤维伤害感受器的优先级是相似的。
They do not occur in the glabrous skin of the hand (where type I AMHs are prevalent).
它们不会出现在手部的无毛皮肤中（I型AMH普遍存在）。
Their mean conduction velocity, 15 m/sec, is also lower than that of type I AMHs.
它们的平均传导速度（15米/秒）也低于I型AMH的传导速度。
Their responses to heat resemble those observed in CMHs, and they may also be mediated by the vanilloid receptor 1 (VR1 or TRPV1).
它们对热的反应类似于在CMH中观察到的反应，它们可能也由辣椒素受体1（VR1或TRPV1）介导。
Responses to endogenous inflammatory/ algesic mediators resemble those seen with type I A-fiber nociceptors (Davis et al 1993b).
对内源性炎症/镇痛介质的反应类似于I型纤维受体的反应（Davis等，1993b）。
Figure 1-3. A-fiber nociceptors exhibit two types of responses to a heat stimulus. A, Scatter plot of peak discharge latency versus response latency for mechanically insensitive afferents (MIAs; purple symbols) and mechanically sensitive afferents (MSAs; green symbols) in response to a 53°C, 30-second stimulus. Receptors that had a long peak discharge latency were considered to have a type I heat response (squares). Receptors that had a short response latency and a peak discharge near stimulus onset were considered to have a type II heat response (circles). The type II heat response was found more frequently in the MIA group (p ≤ 0.05, χ2-test). B, Average peristimulus frequency histogram (obtained with a 0.2-second bin width) of the response to the 53°C, 30-second stimulus for A-fiber nociceptors that had a type I heat response. C, Average peristimulus frequency histogram for A-fiber nociceptors that had a type II heat response. (Reproduced with permission from Treede RD, Meyer RA, Campbell JN 1998 Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties. Journal of Neurophysiology 80:1082–1093.)
Figure 1-3. A纤维伤害感受器表现出对热刺激的两种类型的反应。A，响应于53℃，30秒刺激的机械不敏感传入纤维（MIA; 紫色符号）和机械敏感传入纤维（MSA; 绿色符号）的峰值放电潜伏期与响应潜伏期的散点图。具有长峰值放电潜伏期的受体被认为具有I型热响应（正方形）。具有短响应潜伏期和刺激开始附近的峰值放电的受体被认为具有II型热反应（圆圈）。在MIA组中更频繁地发现II型热反应（p≤0.05，χ2-检验）。B，对具有I型热响应的A-纤维伤害感受器的53℃，30秒刺激的响应的平均外周刺激频率直方图（组距0.2秒）。C，具有II型热响应的A纤维伤害感受器的平均外周刺激频率直方图。(Reproduced with permission from Treede RD, Meyer RA, Campbell JN 1998 Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties. Journal of Neurophysiology 80:1082–1093.)
Examples of the differing responses of the two types of A-fiber nociceptors to a heat stimulus are shown in Figure 1-3.
两种类型的A纤维伤害感受器对热刺激的不同反应的例子如 Figure 1-3所示。
Type I fibers exhibit a distinctive, gradually increasing response to heat.
I型纤维具有独特的，逐渐增加的对热的响应。
They sensitize to burn and chemical injury and probably play a role in the development of hyperalgesia.
它们对烧灼和化学损伤敏感，并可能在痛觉过敏的发展过程中起作用。
Type II fibers respond to heat in similar fashion to CMHs: early peak frequency and a slowly adapting response (Treede et al 1995).
II型纤维与CMH响应热刺激的方式类似：早期频率达到峰值以及缓慢适应（Treede等1995）。
As noted later, type II A-fiber nociceptors are thought to signal first pain sensation in response to heat and may also contribute to pain caused by the application of capsaicin to the skin (Ringkamp et al 2001).
如后所述，II型A纤维伤害感受器被认为是对热反应的第一次疼痛感，并且还可能参与了辣椒素应用于皮肤所引起的疼痛（Ringkamp等2001）。
The conduction velocity of small myelinated Aδ fibers is, by definition, faster than that of unmyelinated C fibers.
根据定义，小有髓鞘Aδ纤维的传导速度快于无髓鞘C纤维的传导速度。
However, the terminal cutaneous branches of nociceptive Aδ fibers may conduct at a velocity characteristic of unmyelinated fibers (i.e., <2 m/sec) (Peng et al 1999).
然而，伤害感受性Aδ纤维的末梢皮肤分支可以以无髓纤维的速度特征传导（即<2米/秒）（Peng等1999）。
In addition, these unmyelinated terminals may branch off the main axon several centimeters proximal to their cutaneous receptive field.
此外，这些无髓鞘的末梢可以在其皮肤感受域附近几厘米处分支出主轴突。
作者: 布鲁克斯 时间: 2020-2-23 11:01
你好什么时候再更新
作者: jiashaliuliu 时间: 2024-9-1 15:29
什么时候再更新
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