Lee-Kubli Corinne A G, Calcutt Nigel A
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA Graduate School of Biomedical Sciences, Sanford-Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Pain. 2014 Feb;155(2):250-260. doi: 10.1016/j.pain.2013.10.001. Epub 2013 Oct 5.
The unpredictable efficacy of current therapies for neuropathic pain may reflect diverse etiological mechanisms operating between, and within, diseases. As descriptions of pain rarely establish specific mechanisms, a tool that can identify underlying causes of neuropathic pain would be useful in developing patient-specific treatments. Rate-dependent depression (RDD), a measure of the change in amplitude of the Hoffman reflex over consecutive stimulations, is attenuated in diabetic rats that also exhibit impaired spinal γ-aminobutyric acid (GABA)A receptor function, reduced spinal potassium chloride co-transporter (KCC2) expression, and indices of painful neuropathy. To investigate whether loss of RDD is a reliable indicator of the contribution of spinal GABAergic dysfunction to neuropathic pain, we assessed RDD, tactile allodynia, and formalin-evoked hyperalgesia in 3 models: rats treated acutely with brain-derived neurotrophic factor (BDNF), diabetic rats treated with the BDNF-sequestering molecule tyrosine receptor kinase B/Fc (TrkB/Fc), and rats with paclitaxel-induced neuropathy. Delivery of BDNF to the spinal cord of normal rats produced RDD deficits and features of painful neuropathy associated with disrupted GABAA receptor-mediated inhibitory function and reduced dorsal spinal KCC2 expression. Treating diabetic rats with TrkB/Fc restored RDD and alleviated indices of painful neuropathy. In paclitaxel-treated rats, RDD was not impaired and behavioral indices of neuropathic pain were not associated with spinal GABAergic dysfunction or reduced dorsal spinal KCC2 expression. Our data reveal BDNF as part of the mechanism underlying spinal cord disinhibition caused by altered GABAA receptor function in diabetic rats and suggest that RDD deficits may be a useful indicator of neuropathic pain states associated with spinal disinhibition, thereby revealing specific therapeutic targets.
目前用于治疗神经性疼痛的疗法疗效不可预测，这可能反映了不同疾病之间以及疾病内部存在的多种病因机制。由于对疼痛的描述很少能确定具体机制，因此一种能够识别神经性疼痛潜在病因的工具，将有助于开发针对患者的个性化治疗方案。速率依赖性抑制（RDD）是衡量连续刺激下霍夫曼反射幅度变化的指标，在糖尿病大鼠中减弱，这些大鼠还表现出脊髓γ-氨基丁酸（GABA）A受体功能受损、脊髓氯化钾共转运体（KCC2）表达降低以及疼痛性神经病变的指标。为了研究RDD的丧失是否是脊髓GABA能功能障碍导致神经性疼痛的可靠指标，我们在3种模型中评估了RDD、触觉异常性疼痛和福尔马林诱发的痛觉过敏：急性接受脑源性神经营养因子（BDNF）治疗的大鼠、用BDNF隔离分子酪氨酸受体激酶B/Fc（TrkB/Fc）治疗的糖尿病大鼠以及患有紫杉醇诱导性神经病变的大鼠。向正常大鼠脊髓注射BDNF会导致RDD缺陷以及与GABAA受体介导的抑制功能破坏和脊髓背侧KCC2表达降低相关的疼痛性神经病变特征。用TrkB/Fc治疗糖尿病大鼠可恢复RDD并减轻疼痛性神经病变指标。在紫杉醇治疗的大鼠中，RDD未受损，神经性疼痛的行为指标与脊髓GABA能功能障碍或脊髓背侧KCC2表达降低无关。我们的数据表明，BDNF是糖尿病大鼠中GABAA受体功能改变导致脊髓去抑制的潜在机制的一部分，并表明RDD缺陷可能是与脊髓去抑制相关的神经性疼痛状态的有用指标，从而揭示了特定的治疗靶点。
