Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Neurosci. 2012 May 16;32(20):6795-807. doi: 10.1523/JNEUROSCI.1017-12.2012.
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.
糖尿病性神经病理性疼痛给个人和社会带来了巨大负担，是一个主要的公共卫生问题。尽管采取了积极的措施，但糖尿病性神经病理性疼痛通常对现有临床治疗方法具有抗性。先前已经在中枢神经系统和周围神经系统损伤性神经病理性疼痛模型中证明了异常树突棘可塑性与疼痛之间存在结构-功能联系。在这里，我们推断如果树突棘重塑有助于糖尿病性神经病理性疼痛，那么（1）畸形棘突的存在应该与疼痛的发展相一致，并且（2）破坏异常的棘突结构应该会减轻慢性疼痛。为了确定树突棘重塑是否有助于链脲佐菌素（STZ）诱导的糖尿病大鼠的神经病理性疼痛，我们分析了树突棘形态以及神经病理性疼痛的电生理和行为迹象。我们的结果表明，在糖尿病中，背角 IV-V 层中的宽动态范围（WDR）神经元中的树突棘形状、分布和形状发生了变化。这些糖尿病引起的变化伴随着 WDR 神经元的过度兴奋和疼痛阈值在 4 周时降低。用 NSC23766（N（6）-[2-[[4-（二乙氨基）-1-甲基丁基]氨基]-6-甲基-4-嘧啶基]-2-甲基-4,6-喹啉二胺三盐酸盐）进行治疗，这是一种已知可以干扰棘突可塑性的 Rac1 特异性抑制剂，可减少糖尿病中畸形棘突的存在，减弱神经元对周围刺激的超反应性，降低 WDR 神经元的自发放电活动，并改善伤害性机械痛阈值。在 STZ 注射后 1 周，伴有高血糖但没有疼痛证据的动物的棘突形态变化很少或没有。这些结果表明，糖尿病引起的适应性树突棘重塑在神经病理性疼痛中具有机制作用。控制棘突形态发生和可塑性的分子途径可能是有前途的未来治疗靶点。
