Lee-Kubli Corinne A, Calcutt Nigel A
Graduate School of Biomedical Sciences, Sanford-Burnham Institute for Molecular Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
Handb Clin Neurol. 2014;126:533-57. doi: 10.1016/B978-0-444-53480-4.00034-5.
Painful neuropathy, like the other complications of diabetes, is a growing healthcare concern. Unfortunately, current treatments are of variable efficacy and do not target underlying pathogenic mechanisms, in part because these mechanisms are not well defined. Rat and mouse models of type 1 diabetes are frequently used to study diabetic neuropathy, with rats in particular being consistently reported to show allodynia and hyperalgesia. Models of type 2 diabetes are being used with increasing frequency, but the current literature on the progression of indices of neuropathic pain is variable and relatively few therapeutics have yet been developed in these models. While evidence for spontaneous pain in rodent models is sparse, measures of evoked mechanical, thermal and chemical pain can provide insight into the pathogenesis of the condition. The stocking and glove distribution of pain tantalizingly suggests that the generator site of neuropathic pain is found within the peripheral nervous system. However, emerging evidence demonstrates that amplification in the spinal cord, via spinal disinhibition and neuroinflammation, and also in the brain, via enhanced thalamic activity or decreased cortical inhibition, likely contribute to the pathogenesis of painful diabetic neuropathy. Several potential therapeutic strategies have emerged from preclinical studies, including prophylactic treatments that intervene against underlying mechanisms of disease, treatments that prevent gains of nociceptive function, treatments that suppress enhancements of nociceptive function, and treatments that impede normal nociceptive mechanisms. Ongoing challenges include unraveling the complexity of underlying pathogenic mechanisms, addressing the potential disconnect between the perceived location of pain and the actual pain generator and amplifier sites, and finding ways to identify which mechanisms operate in specific patients to allow rational and individualized choice of targeted therapies.
疼痛性神经病变与糖尿病的其他并发症一样，正日益引起医疗保健领域的关注。不幸的是，目前的治疗方法疗效各异，且未针对潜在的致病机制，部分原因是这些机制尚未明确界定。1型糖尿病的大鼠和小鼠模型常用于研究糖尿病性神经病变，尤其有报道称大鼠持续出现痛觉过敏和痛觉超敏。2型糖尿病模型的使用频率越来越高，但目前关于神经性疼痛指标进展的文献参差不齐，且在这些模型中开发的治疗方法相对较少。虽然啮齿动物模型中自发性疼痛的证据稀少，但诱发的机械性、热性和化学性疼痛测量可以为该病的发病机制提供见解。疼痛呈袜套样和手套样分布，这诱人地表明神经性疼痛的产生部位位于周围神经系统。然而，新出现的证据表明，脊髓通过脊髓去抑制和神经炎症的放大作用，以及大脑通过丘脑活动增强或皮质抑制减弱，可能都有助于疼痛性糖尿病神经病变的发病机制。临床前研究已经出现了几种潜在的治疗策略，包括针对疾病潜在机制的预防性治疗、防止伤害感受功能增强的治疗、抑制伤害感受功能增强的治疗以及阻碍正常伤害感受机制的治疗。目前面临的挑战包括解开潜在致病机制的复杂性、解决疼痛感知位置与实际疼痛产生和放大部位之间可能存在的脱节问题，以及找到方法来确定哪些机制在特定患者中起作用，以便合理且个性化地选择靶向治疗方法。
