J Neurosci：耶鲁大学研究者发现糖尿病性神经痛的新靶点

科学日报（2012-05-15）——将近半数的糖尿病患者饱受神经性疼痛的折磨——一种难治的、棘手的的并发症。目前，耶鲁的研究人员明确了一种令人意想不到的疼痛机制以及缓解这种疼痛的潜在治疗靶点。

来自耶鲁和西部港口退伍军人事务医学中心的研究团队在5月15日的《神经科学杂志》上阐述了糖尿病大鼠树突棘（神经细胞接收分支上的微小突起）结构性变化与疼痛相关的机理。

耶鲁医学院神经病学副研究员，同时也是这些研究的主要作者Andrew Tan说：“糖尿病导致神经性疼痛的机理仍然是个迷。本研究的创新点在于提出这样一种想法，即神经性疼痛是因疼痛反射环路折返功能所致。”

随着糖尿病患者的日益增多，糖尿病性神经痛也亟需得到治疗，而且后者一旦发作，就是终身性的。

Tan说：“树突棘起初在记忆环路功能中被人们研究，而我们发现他们同样在糖尿病的疼痛感知中发挥作用”。单个神经元可能包含数百至数千的树突棘。

由Tan率领的耶鲁团队以及神经生物学和药学教授、神经病学的布里吉玛丽弗莱厄蒂教授、高级作者Stephen G. Waxman博士发现：异常的树突棘与疼痛的发生、维持相关。他们同样发现在实验动物模型上，一种干扰这些树突棘形成的药物可以减少疼痛的发生，这提示异常的树突棘可能是治疗靶点。

Tan认为，如同他们在人类大脑记忆和学习中起的关键性作用一样，这些树突棘可能还会储存/保留疼痛印记。

Waxman说：“我们明确了单个的、可以控制树突棘结构性改变的关键分子，并且我们很有希望开拓一种治疗手段，能够干预该分子以减少糖尿病性疼痛的发生。”

论文上的其他作者有Omar A. Samad、Tanya Z. Fischer、Peng Zhao和Anna-Karin Persson。

该研究受退伍军人事务部资助。

Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain.

J Neurosci 2012;3220:6795-807

Tan AM Samad OA Fischer TZ Zhao P Persson AK Waxman SG

Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516.

Abstract
Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.