Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this “disease of pain.” Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na⁺, K⁺, Ca²⁺, hyperpolarization-activated cyclic nucleotide–gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the α2δ-1 subunit of voltage-gated Ca²⁺ channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.

中文翻译：

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神经性疼痛的病因和药理

对神经系统的伤害或疾病会引起慢性的，有时甚至是顽固的神经性疼痛。许多并行，相互依存和随时间变化的过程，包括外周，脊髓上和脊髓水平的神经免疫相互作用，都导致了这种“疼痛疾病”的病因。最近的工作强调了集落刺激因子1，ATP和脑源性神经营养因子的作用。在脊髓背角和整个体感系统中，兴奋过程得以增强，抑制过程得以减弱。这导致中枢敏化和异常处理，从而使触觉和无害的热信息被认为是疼痛（异常性疼痛）。神经性疼痛发作的过程与长期维持过程不同。阿片类药物显示出有限的功效，不到35％的患者从其他治疗方法中获得了有意义的收益。因此，我们回顾了过去20年来出现的有希望的治疗靶点，包括Na⁺，K ⁺，Ca ²⁺，超极化激活的环状核苷酸门控通道，瞬时受体电位通道类型V1通道和腺苷A3受体。尽管取得了这些进展，加巴喷丁类药物仍保留其作为一线治疗的地位，但对其作用机理了解甚少。我们概述了在了解神经性疼痛的病因学方面的最新进展，并显示了这如何为普瑞巴林和加巴喷丁的细胞作用提供了见识。与gabapentinoids的相互作用α 2 δ电压-门控的Ca -1亚基²⁺通道在脊髓和更高的中心产生多种神经元类型的特定作用。我们建议影响多个过程而不是单个特定靶标的药物显示出未来治疗发展的最大希望。