Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a “gift” because it both protects our body from harm and allows healing of damaged tissues [1]. Damage to tissues from trauma or disease can result in distorted or amplified nociceptor signaling and sensitization of the spinal cord and brain (Central Nervous System; CNS) pathways to normal input from light touch mechanoreceptors. Together, these processes can result in nagging to unbearable chronic pain and extreme sensitivity to light skin touch (allodynia). Unlike acute protective pain, chronic pain and allodynia serve no useful purpose and can severely reduce the quality of life of an affected person. Chronic pain can arise from impairment to peripheral neurons, a phenomenon called “peripheral neuropathic pain.” Peripheral neuropathic pain can be caused by many insults that directly affect peripheral sensory neurons, including mechanical trauma, metabolic imbalance (e.g., diabetes), autoimmune diseases, chemotherapeutic agents, viral infections (e.g., shingles). These insults cause “acquired” neuropathies such as small-fiber neuropathies, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and post herpetic neuralgia. Peripheral neuropathic pain can also be caused by genetic factors and result in hereditary neuropathies that include Charcot-Marie-Tooth disease, rare channelopathies and Fabry disease. Many acquired and hereditary neuropathies affect the skin, our largest organ and protector of nearly our entire body. Here we review how cutaneous nociception (pain perceived from the skin) is altered following diseases that affect peripheral nerves that innervate the skin. We provide an overview of how noxious stimuli are detected and encoded by molecular transducers on subtypes of cutaneous afferent endings and conveyed to the CNS. Next, we discuss several acquired and hereditary diseases and disorders that cause painful or insensate (lack of sensation) cutaneous peripheral neuropathies, the symptoms and percepts patients experience, and how cutaneous afferents and other peripheral cell types are altered in function in these disorders. We highlight exciting new research areas that implicate non-neuronal skin cells, particularly keratinocytes, in cutaneous nociception and peripheral neuropathies. Finally, we conclude with ideas for innovative new directions, areas of unmet need, and potential opportunities for novel cutaneous therapeutics that may avoid CNS side effects, as well as ideas for improved translation of mechanisms identified in preclinical models to patients.

我们快速检测和应对有害环境刺激的能力对于我们的安全和生存至关重要。这种固有的急性疼痛检测是一份“礼物”，因为它既可以保护我们的身体免受伤害，又可以治愈受损的组织[1]。创伤或疾病造成的组织损伤可能会导致伤害感受器信号传导扭曲或放大，以及脊髓和大脑（中枢神经系统；CNS）光触机械感受器正常输入通路的敏感化。这些过程共同导致难以忍受的慢性疼痛和对轻微皮肤接触的极度敏感（异常性疼痛）。与急性保护性疼痛不同，慢性疼痛和异常性疼痛没有任何作用，并且会严重降低受影响者的生活质量。慢性疼痛可能是由周围神经元受损引起的，这种现象称为“周围神经性疼痛”。周围神经性疼痛可由许多直接影响周围感觉神经元的损伤引起，包括机械性创伤、代谢失衡（例如糖尿病）、自身免疫性疾病、化疗药物、病毒感染（例如带状疱疹）。这些损伤会导致“获得性”神经病，例如小纤维神经病、糖尿病性神经病、化疗引起的周围神经病和带状疱疹后神经痛。周围神经性疼痛也可由遗传因素引起，并导致遗传性神经病，包括夏科-马里-图思病、罕见通道病和法布里病。许多获得性和遗传性神经病都会影响皮肤，皮肤是我们最大的器官，也是几乎整个身体的保护者。在这里，我们回顾一下在影响支配皮肤的周围神经的疾病之后，皮肤伤害感受（从皮肤感知到的疼痛）是如何改变的。我们概述了皮肤传入末梢亚型上的分子传感器如何检测和编码有害刺激并将其传递到中枢神经系统。接下来，我们讨论几种导致疼痛或无感觉（缺乏感觉）皮肤周围神经病的获得性和遗传性疾病和病症、患者经历的症状和感知，以及皮肤传入细胞和其他外周细胞类型在这些疾病中功能如何改变。我们重点介绍令人兴奋的新研究领域，这些领域涉及非神经元皮肤细胞，特别是角质形成细胞，与皮肤伤害感受和周围神经病变有关。最后，我们总结了关于创新新方向、未满足需求领域的想法，以及可能避免中枢神经系统副作用的新型皮肤治疗的潜在机会，以及改进临床前模型中确定的机制向患者转化的想法。