Millan M J
Institut de Recherches Servier, Psychopharmacology Department, Paris, France.
Prog Neurobiol. 1999 Jan;57(1):1-164. doi: 10.1016/s0301-0082(98)00048-3.
The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although acute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar inflammatory mediators, such as prostaglandins and bradykinin, potentially-important, pronociceptive roles have been proposed for a variety of 'exotic' species, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role in the response to inflammation and injury, and in processes modifying nociception. In the dorsal horn of the spinal cord, wherein the primary processing of nociceptive information occurs, N-methyl-D-aspartate receptors are activated by glutamate released from nocisponsive afferent fibres. Their activation plays a key role in the induction of neuronal sensitization, a process underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exacerbates sensitized states and further enhance nociception. As concerns the transfer of nociceptive information to the brain, several pathways other than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-sensory' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involved in the induction of pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive information from peripheral nerve terminals to the dorsal horn, and therefrom to higher centres, are outlined. This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.
疼痛这种极不愉快的感觉源自一系列极其复杂且相互作用的机制，这些机制在神经轴的各个层面整合，从外周经背角到更高层次的脑结构。疼痛通常由特定伤害感受器的激活引发（“伤害性疼痛”）。然而，它也可能源于感觉纤维的损伤，或中枢神经系统本身的损害（“神经性疼痛”）。尽管急性和亚慢性伤害性疼痛起到一种警示作用，但慢性和/或严重的伤害性疼痛以及神经性疼痛是适应不良的。近年来，诱导疼痛背后的神经解剖回路和细胞机制已逐渐明晰。除了诸如前列腺素和缓激肽等常见的炎症介质外，多种“外来”物质，包括质子、三磷酸腺苷、细胞因子、神经营养因子（生长因子）和一氧化氮，也被认为具有潜在的重要促痛作用。此外，无论是在外周还是中枢神经系统，已证实非神经元的神经胶质细胞和免疫活性细胞在对炎症和损伤的反应以及改变痛觉的过程中发挥调节作用。在脊髓背角，伤害性信息在此进行初级处理，N - 甲基 - D - 天冬氨酸受体被对伤害刺激有反应的传入纤维释放的谷氨酸激活。它们的激活在神经元敏化的诱导过程中起关键作用，而神经元敏化是导致长期疼痛状态的一个过程。此外，在周围神经损伤后，背角抑制性中间神经元张力的降低会加剧敏化状态并进一步增强痛觉。关于伤害性信息向大脑的传递，除了经典的脊髓丘脑束外，其他几条通路也很重要：例如，突触后背柱通路。在讨论脊髓以上结构在痛觉中的作用时，应强调其“辨别性感觉”和“情感认知”维度之间的差异。本文的目的是全面阐述参与疼痛诱导的机制。特别关注细胞层面以及周围神经损伤的后果。在综述的第一部分，概述了伤害性信息从外周神经末梢传递到背角，再从此传递到更高中枢的神经元通路。然后利用这个神经元框架来探讨通过刺激外周伤害感受器、周围神经损伤以及中枢神经系统本身的损害而诱导疼痛所涉及的外周、脊髓和脊髓以上机制。最后，提出一个假说，即神经营养因子可能在调节痛觉的中枢适应性机制中发挥重要作用。对疼痛起源的更好理解应有助于开发更有效的治疗新策略。
