Current and Future Issues in the Development of Spinal Agents for the Management of Pain.
Current and Future Issues in the Development of Spinal Agents for the Management of Pain.
复制标题
DOI：
10.2174/1570159x14666160307145542
复制
发表时间：
2017
影响因子：
5.3
通讯作者：
Wiese AJ
中科院分区：
文献类型：
--
作者：
Yaksh TL;Fisher CJ;Hockman TM;Wiese AJ
靶向用于脊髓递送的镇痛药物反映了这样的事实，即虽然疼痛的有意识体验是在棘上介导的，但由高强度刺激、组织损伤和/或神经损伤引发的输入在脊髓背角水平编码，并且该输出告知大脑关于外周环境。这种编码过程受到强烈的上调，导致感觉过敏状态和下调，减少伤害性刺激的正在进行的处理，逆转感觉过敏和疼痛处理。本综述讨论了脊髓伤害性处理的生物学相关的影响，鞘内给药的药物在改变疼痛处理后急性刺激，组织炎症/损伤和神经损伤。综述包括i）目前用作鞘内镇痛药的主要脊柱药物类别（阿片类激动剂、α 2激动剂、钠通道阻滞剂、钙通道阻滞剂、NMDA阻滞剂、GABA A/B激动剂、考克斯抑制剂; ii）脊柱治疗药理学的持续发展，重点关注研究较少的药物/靶点（胆碱酯酶抑制;腺苷激动剂; iii）新型鞘内靶向方法，包括基于基因的方法（病毒载体、质粒、干扰RNA）;反义和毒素（肉毒杆菌毒素;树脂毒素，P物质皂草素）;和iv）与鞘内药物递送相关的问题（神经轴药物分布），输注物输送曲线，药物剂量，鞘内给药安全性临床前评价中涉及的处方和原则。
Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.