【原】脊髓电刺激治疗慢性神经病理性疼痛的作用机制、作用靶点和作用模式（一）

 英语晨读 ·

山东省立医院疼痛科英语晨读已经坚持10余年的时间了，每天交班前15分钟都会精选一篇英文文献进行阅读和翻译。一是可以保持工作后的英语阅读习惯，二是可以学习前沿的疼痛相关知识。我们会将晨读内容与大家分享，助力疼痛学习。

本次文献选自Joosten EA, Franken G. Spinal cord stimulation in chronic neuropathic pain: mechanisms of action, new locations, new paradigms. Pain. 2020 Sep;161 Suppl 1(1):S104-S113.本次学习由李芸主治医师主讲。

1. Introduction

Neuropathic pain is a complex, heterogeneous disorder that affects approximately 8% of the total adult human population and comes with significant burden for both the patient and health care system. The international association for the study of pain defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system” and classifies chronic neuropathic pain as a disease under International Classification of Diseases 11th Revision (ICD-11). Despite the development and use of many pharmacological drugs and guidelines for the treatment of chronic neuropathic pain over the years, a substantial amount of neuropathic pain patients remain undertreated or untreated, with less than 50% of patients responding to pharmacological treatment. The development of novel, last-resort interventional treatment therapies is crucial to also relief pain in these refractory patients.

1.前言

神经病理性疼痛是一种复杂的疾病，成年人发病率约为8%，给患者和医疗系统带来了巨大负担。国际疼痛研究协会定义疼痛为由损伤或疾病引起的疼痛躯体感觉神经系统，并在国际疾病分类(ICD-11)中的归类为慢性神经病理性疼痛。尽管多年来慢性神经病理性疼痛的治疗药物和治疗指南都得到了很好的发展，但是还是有很大一部分神经病理性疼痛患者治疗不彻底，甚至未能治疗，药物治疗效果理想患者的比例不到50%。开发新的介入治疗方法对于缓解难治性神经病理性疼痛还是至关重要。

Over the years, spinal cord stimulation (SCS) has proven to be a valuable last-resort treatment option (approximately 50% pain reduction in 50%-70% of patients) for a wide variety of refractory pain disorders, such as painful diabetic peripheral neuropathy (PDPN), complex regional pain syndrome (CRPS), and failed back surgery syndrome (FBSS). The mechanism underlying Tonic SCS (see section 2) is partly understood, and evidence has been provided for a mechanism of action through both spinal (section 2.1) and supraspinal levels (section 2.2). Recently, new physiological targets for stimulation as well as novel SCS paradigms were introduced to bridge the gap between currently achieved pain relief (as obtained with Tonic SCS) and the desired pain relief. Literature on the effect of stimulation at new anatomical locations, such as dorsal root ganglion stimulation (DRGS) (see section 3), and the use of new subsensory SCS paradigms such as high-frequency (HF) SCS (see section 4.2) and Burst SCS (see section 4.3) are discussed. This review ends with concluding remarks and future directions for research.

多年来，脊髓电刺激（SCS）已被证实对各种难治性疼痛有积极的治疗作用（50%-70%的患者疼痛减轻约50%），如疼痛性糖尿病周围神经病变（PDPN）、复杂区域疼痛综合征（CRPS）、和手术失败综合征（FΒSS）等。SCS的作用机制目前还没有充分了解，推测作用机制有2种，分别是脊髓水平机制和脊髓上水平。最近，随着SCS新的生理学靶点以及新的SCS模式的研发，或许可以弥补目前疼痛缓解与期望的疼痛缓解之间的差距，例如SCS作用的新的解剖学靶点（背根节），新型SCS作用模式（高频）和爆冲式SCS等。本综述总结了这些问题和未来的研究方向。

2. Tonic spinal cord stimulation: mechanisms of action

2.1. Tonic spinal cord stimulation and spinal segmental mechanisms

Experimental studies on the effect of SCS have predominantly been performed in rodent models including the partial sciatic nerve ligation model (PSNL) (for review, see Smits et al.). Electrodes are carefully inserted, either transcutaneous or through laminectomy, in the epidural space on top of the dura mater surrounding the spinal cord. Then, electrical pulses are administered to the dorsal columns of the spinal cord through an implantable pulse generator or an external stimulation device. Tonic SCS settings vary within a range of 30 to 80 Hz, 100 to 500 µs of pulse width, and an amplitude above sensory threshold.

2. 传统脊髓电刺激（低频）：作用机制

2.1传统SCS与脊髓水平机制

有关SCS效应的实验研究主要在啮齿动物模型中进行，比如坐骨神经结扎模型。经皮或椎板切除术后将电极小心地放入硬膜外间隙。然后，通过可植入的脉冲发生器或外部刺激装置给脊髓背柱施加电脉冲。传统SCS设置参数为频率30至80 Hz、脉宽100至500 ms和幅度高于感觉阈值，在该范围内波动。

The concept of Tonic SCS emerged as a direct spin‐off from the gate control theory. Based on this gate control theory, it was postulated that antidromic stimulation of the non-nociceptive Aβ fibers in the dorsal columns could close a “spinal gate,” located in the dorsal horn of the spinal cord. Meanwhile, orthodromic stimulation of the Aβ fibers in the dorsal columns also caused paresthesias (ie, abnormal tingling sensation) in the area innervated by the stimulated fibers (Fig. 1). Nowadays, during implantation of the SCS lead the physician makes sure these paresthesias overlap the painful area. Closing of the “spinal gate” is mediated by inhibitory interneurons located in the upper laminae of the dorsal horn. In line with the gate control theory, these inhibitory interneurons, when antidromically activated by Tonic SCS, modulate the nociceptive signal through the release of gamma-aminobutyric acid (GABA). Indeed, experimental research has demonstrated that Tonic SCS decreases intracellular GABA immunoreactivity in the dorsal horn of chronic neuropathic rats. At the same time, extracellular GABA levels in the spinal dorsal horn increase when applying Tonic SCS in chronic neuropathic rats. Thus, enhanced GABA release in the spinal dorsal horn seems to be a vital aspect of the mechanisms underlying Tonic SCS. The mechanism underlying interference with nociception at the spinal cord level using Tonic SCS was further elucidated by the administration of pharmacological agents. Local intrathecal application of a GABAB receptor antagonist in the dorsal horn transiently abolished the stimulation-induced analgesic effect in neuropathic rats, and rats not receiving adequate reductions in tactile allodynia with Tonic SCS (nonresponders) were turned into responders by administration of the GABAB receptor agonist baclofen. The aforementioned preclinical findings were successfully translated to the clinic, where some neuropathic pain patients not responding to Tonic SCS were turned into responders with additional intrathecal administration of low (subeffective) doses of baclofen. Hence, the presynaptic GABAB-mediated inhibition of the communication between nociceptive afferents and the second-order neurons in the spinal dorsal horn is important in the mechanism underlying Tonic SCS. Nevertheless, also postsynaptic GABAergic modulation through GABAA receptors in conjunction with K+/Cl− cotransporter 2 (KCC2) expression is involved in neuropathic pain and in the mechanism underlying Tonic SCS.

传统SCS的概念是从门控理论直接衍生出来的。根据门控理论，逆向刺激脊髓背柱中非伤害性Aβ纤维可以关闭位于脊髓背角的“脊髓门”。 同时，正向刺激背柱中的Aβ纤维也会导致受刺激神经支配区域的感觉异常。在植入SCS电极时，医生要确保这些感觉异常与疼痛区域重叠。“脊髓门”的关闭是由位于背角上层的抑制性中间神经元介导。根据门控理论，这些抑制性中间神经元在被传统SCS逆向激活时，通过释放γ-氨基丁酸（GABA）来调节伤害性信号。实验研究表明，传统SCS降低慢性神经病理性疼痛大鼠脊髓背角神经元内GABA的免疫反应性。同时慢性神经病理性疼痛大鼠应用传统SCS后，脊髓背角细胞外GABA水平升高。因此脊髓背角GABA释放的增加可能是传统SCS作用机制的一个重要方面。通过给药，进一步阐明了传统SCS在脊髓水平上干扰伤害信号的机制。在神经病理性疼痛大鼠的背角局部鞘内应用GABA受体拮抗剂可暂时消除电刺激诱导的镇痛效应，而传统SCS不能缓解的触觉异常疼痛，通过给予GABA受体激动剂巴氯芬后可以缓解疼痛。上述临床前发现已成功转化为临床，一些对传统SCS无反应的神经病理性疼痛患者通过鞘内注射低（但有效）剂量的巴氯芬可以缓解疼痛。因此突触前GABA介导的对伤害性传入和脊髓背角二级神经元之间信号传导的的抑制在传统SCS的作用机制中很重要。除此之外，通过调解GABA受体结合K/Cl共转运蛋白2（KCC2）表达发挥作用的突触后GABA能调节作用也参与了神经性疼痛和传统SCS的机制。