Humble Stephen R
Department of Anaesthetics and Pain Management, Charing Cross Hospital, Imperial College NHS Healthcare Trust London, London, W6 8RF, UK.
F1000Res. 2016 Aug 5;5:1923. doi: 10.12688/f1000research.9034.1. eCollection 2016.
Peripheral and central sensitisation are implicated in the development of neuropathic pain. Hypersensitivity of pain pathway neurons has been described in animal models of diabetic neuropathy, which is postulated to be related to an imbalance between inhibitory and excitatory signals within the spinal cord. GABAergic neurons within the pain pathway are vital for the transmission of painful stimuli to higher centres. A developmental change in the rate of exponential decay of GABAergic synaptic events has been observed in other types of neurons and this may be associated with fluctuations in endogenous neurosteroid tone. Methods: The whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from wild type mice between the ages of 6 and 80 days in the spinal cord, the nucleus reticularis of the thalamus and the cerebral cortex. Recordings were also obtained from mice with diabetic neuropathy (ob/ob and db/db) between the ages of 60 and 80 days. Behavioural experiments were performed to examine mechanical and thermal nociception.
Electrophysiological recordings from cortical pain pathway neurons from mature type-2 diabetic mice revealed that the endogenous neurosteroid tone is reduced compared to control. However, selected neurosteroid compounds had a more pronounced effect on the GABA receptors of these diabetic mice. ob/ob mice exhibit mechanical hyperalgesia and allodynia, which was reduced by neurosteroids applied exogenously.
The reduced endogenous neurosteroid tone in ob/ob mice may be linked to their hypersensitivity. Neurosteroids may exert analgesic effects in pathological pain states by attempting to restore the physiological GABAergic inhibitory tone.
外周和中枢敏化与神经性疼痛的发生有关。在糖尿病性神经病变的动物模型中，已描述了疼痛通路神经元的超敏反应，据推测这与脊髓内抑制性和兴奋性信号之间的失衡有关。疼痛通路中的γ-氨基丁酸（GABA）能神经元对于将疼痛刺激传递至更高中枢至关重要。在其他类型的神经元中已观察到GABA能突触事件指数衰减率的发育变化，这可能与内源性神经甾体水平的波动有关。
对神经组织切片使用全细胞膜片钳技术。从6至80日龄野生型小鼠的脊髓、丘脑网状核和大脑皮质获取电生理记录。还从60至80日龄的糖尿病性神经病变小鼠（ob/ob和db/db）获取记录。进行行为实验以检查机械性和热性伤害感受。
来自成熟2型糖尿病小鼠皮质疼痛通路神经元的电生理记录显示，与对照组相比，内源性神经甾体水平降低。然而，选定的神经甾体化合物对这些糖尿病小鼠的GABA受体有更明显的作用。ob/ob小鼠表现出机械性痛觉过敏和异常性疼痛，外源性应用神经甾体可减轻这些症状。
ob/ob小鼠内源性神经甾体水平降低可能与其超敏反应有关。神经甾体可能通过试图恢复生理性GABA能抑制作用，在病理性疼痛状态中发挥镇痛作用。
