The sensation of itch is difficult to define but is generally accepted as an unpleasant cutaneous sensation, leading to the desire to scratch. It has clear survival value as it has been conserved across many mammalian species through different evolutionary pathways. There are many different manifestations of itch or other related sensations, such as tingling, crawling, or irritation. Some of these more diffuse sensations are initiated in the central nervous system (CNS), but most originate from the periphery, in particular, the skin. Cutaneous itch has many different causes and triggers, and it is crucial to understand that the interactions between the peripheral nonmyelinated, sensory C-fibers and different skin cells is the initial step for the initiation of the itch sensation in skin. Numerous skin cells are involved in this nerve–skin interaction, ranging from keratinocytes, melanocytes, Merkel cells, Langerhans cells to various dermal cells such as mastocytes, endothelial cells, fibroblasts, and cells in skin appendages. In previous publications we proposed the existence of a keratinocyte-nerve “unit,” consisting of very fine and superficial nerve fibers in the epidermis connecting to keratinocytes that may be specialized in function. These keratinocytes could act as sensors and send signals either to other keratinocytes or to the epidermal C-fibers. The interaction between different cell systems in the epidermis might be crucial for the initiation of various peripheral sensations such as pain, itching, burning, tickling, and tingling. All these sensations have very distinct functions, but most of these sensation qualities do not require an immediate reflex mechanical withdrawal reaction such as the stimulation of dermal myelinated A-delta fibers with conduction of deep, well-defined injuries. Sensations such as itching, not well localized pain burning, tickling or tingling are danger signals that do not require an immediate withdrawal action but rather notify of a danger that needs to be removed by swiping or scratching. This clearly implies that the skin has very sophisticated mechanisms to sense different levels of danger and to react in different ways. The brain provides a conscious realization that there is a sensation of itch, after which we will react by rubbing or scratching to remove the noxious stimulus. The itch signal from the periphery will be modulated during its journey through the peripheral nerves, dorsal root ganglia and spinal cord to the higher centers in the brain. Inflammation of the skin as well as constant stimulation of the peripheral nerve system will modify signals emanating from the skin and in transmission of these signals to the CNS; indeed, the threshold and the irritability of the nerve fibers will change under the influence of various cytokines, growth factors, neuropeptides, and neurotransmitters. The different perceptions of itch and pain seem to have very distinct pathways in the CNS. The removal of pain is not a prerequisite for induction of itch (Liu et al. 2011). It is very difficult to separate the peripheral events in itch and pain from the processes in the CNS, but it is clear that these various sensations can be modulated at every level of transduction (Sun and Chen 2007). The events in the periphery appear to be equally important as mechanisms occurring in the CNS, and this is especially true for the involvement of the opioid receptor system in modulation of sensory function both in the periphery and CNS. While the opioid system, and in particular its influence on pain, has been well studied in the CNS, very little is known about the role of opioid receptors in skin, and in addition we are at the infancy of understanding the nerve systems in the skin. The goal of this chapter is to describe the role of the opioid receptor system in the induction and regulation of the peripheral components of pain and itching mechanisms, with strong focus on itch. Also discussed are possibilities of treating very cumbersome sensations (itch, pain, and tingling) that have been peripherally induced by topical applications of opioids, with the intention of limiting the side effects generated by opioidergic activity within the CNS.
瘙痒的感觉很难定义，但通常被认为是一种令人不适的皮肤感觉，会引发搔抓的欲望。它具有明确的生存价值，因为它在许多哺乳动物物种中通过不同的进化途径得以保留。瘙痒或其他相关感觉有许多不同的表现形式，如刺痛、蠕动感或刺激感。其中一些较为弥散的感觉在中枢神经系统（CNS）中引发，但大多数起源于外周，特别是皮肤。皮肤瘙痒有许多不同的原因和触发因素，关键是要明白外周无髓鞘感觉C纤维与不同皮肤细胞之间的相互作用是皮肤中瘙痒感觉起始的第一步。许多皮肤细胞参与了这种神经 - 皮肤相互作用，从角质形成细胞、黑素细胞、默克尔细胞、朗格汉斯细胞到各种真皮细胞，如肥大细胞、内皮细胞、成纤维细胞以及皮肤附属器中的细胞。在之前的出版物中，我们提出存在一种角质形成细胞 - 神经“单元”，由表皮中非常细且浅表的神经纤维连接到可能功能特殊的角质形成细胞组成。这些角质形成细胞可以充当传感器，并向其他角质形成细胞或表皮C纤维发送信号。表皮中不同细胞系统之间的相互作用可能对于引发各种外周感觉，如疼痛、瘙痒、灼烧、瘙痒和刺痛至关重要。所有这些感觉都有非常独特的功能，但这些感觉特性中的大多数并不需要立即产生反射性机械退缩反应，例如刺激真皮有髓鞘A - δ纤维传导深部、明确界定的损伤。诸如瘙痒、定位不明确的疼痛、灼烧、瘙痒或刺痛等感觉是危险信号，不需要立即采取退缩行动，而是通知需要通过擦拭或搔抓来消除的危险。这清楚地表明皮肤具有非常复杂的机制来感知不同程度的危险并以不同方式做出反应。大脑会有意识地意识到存在瘙痒感，之后我们会通过摩擦或搔抓来做出反应以去除有害刺激。来自外周的瘙痒信号在通过外周神经、背根神经节和脊髓传递到大脑更高中枢的过程中会受到调节。皮肤炎症以及外周神经系统的持续刺激会改变从皮肤发出并在将这些信号传递到中枢神经系统时的信号；实际上，神经纤维的阈值和兴奋性会在各种细胞因子、生长因子、神经肽和神经递质的影响下发生变化。瘙痒和疼痛的不同感知在中枢神经系统中似乎有非常不同的途径。消除疼痛不是引发瘙痒的先决条件（Liu等人，2011年）。很难将瘙痒和疼痛中的外周事件与中枢神经系统中的过程区分开来，但很明显这些各种感觉在转导的每个层面都可以受到调节（Sun和Chen，2007年）。外周的事件似乎与中枢神经系统中发生的机制同样重要，对于阿片受体系统在外周和中枢神经系统中调节感觉功能的参与尤其如此。虽然阿片系统，特别是其对疼痛的影响，在中枢神经系统中已经得到了充分研究，但关于阿片受体在皮肤中的作用知之甚少，此外我们对皮肤中的神经系统的了解还处于起步阶段。本章的目的是描述阿片受体系统在疼痛和瘙痒机制外周成分的诱导和调节中的作用，重点是瘙痒。还讨论了通过局部应用阿片类药物在外周诱导的非常麻烦的感觉（瘙痒疼痛和刺痛）的治疗可能性，目的是限制中枢神经系统内阿片能活性产生的副作用。
