King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.
Pharmacol Biochem Behav. 2013 Oct;111:30-6. doi: 10.1016/j.pbb.2013.08.003. Epub 2013 Aug 17.
We studied the hypothesis that spinal d-amino acid oxidase (DAAO) that is expressed in astrocytes and that has been reported to promote tonic pain in various pathophysiological conditions plays a role in 'physiological' pain hypersensitivity induced by rapid eye movement sleep deprivation (REMSD). The experiments were performed in healthy rats with a chronic intrathecal (i.t.) catheter. Pain behavior was assessed by determining limb withdrawal response to repetitive stimulation of the hind paw with a calibrated series of monofilaments. REMSD of 48 h duration produced a significant mechanical hypersensitivity. At 48 h of REMSD, the animals were treated i.t. with a DAAO inhibitor or vehicle. Three structurally different DAAO inhibitors were tested in this study: 6-chlorobenzo[d]isoxazol-3-ol (CBIO), sodium benzoate, and 5-methylpyrazole-3-carboxylic acid (AS-057278). CBIO (1-3 μg), sodium benzoate (30-100 μg) and AS-057278 (3-10 μg) produced dose-related antihypersensitivity effects in sleep-deprived animals. In control animals (with no sleep deprivation), the currently used doses of DAAO inhibitors failed to produce significant changes in mechanically evoked pain behavior. The results indicate that among spinal pain facilitatory mechanisms that contribute to the sleep deprivation-induced mechanical pain hypersensitivity is DAAO, presumably due to production of reactive oxygen species, such as hydrogen peroxide, an endogenous agonist of the pronociceptive TRPA1 ion channel.
我们研究了这样一个假设，即在星形胶质细胞中表达的、已被报道在各种病理生理条件下促进紧张性疼痛的脊髓 D-氨基酸氧化酶（DAAO），在快速眼动睡眠剥夺（REMSD）引起的“生理性”疼痛过敏中发挥作用。实验在具有慢性鞘内（i.t.）导管的健康大鼠中进行。通过确定对后爪进行重复刺激时的肢体退缩反应来评估疼痛行为，使用一系列校准的单丝。持续 48 小时的 REMSD 导致明显的机械性超敏反应。在 REMSD 48 小时时，动物通过鞘内给予 DAAO 抑制剂或载体进行治疗。本研究测试了三种结构不同的 DAAO 抑制剂：6-氯苯并[d]异恶唑-3-醇（CBIO）、苯甲酸钠和 5-甲基吡唑-3-羧酸（AS-057278）。CBIO（1-3μg）、苯甲酸钠（30-100μg）和 AS-057278（3-10μg）在睡眠剥夺动物中产生剂量相关的抗超敏反应作用。在对照动物（无睡眠剥夺）中，目前使用的 DAAO 抑制剂剂量未能引起机械诱发疼痛行为的显著变化。结果表明，在导致睡眠剥夺引起的机械性疼痛过敏的脊髓疼痛促进机制中，DAAO 是其中之一，可能是由于产生了活性氧，如过氧化氢，这是促伤害性 TRPA1 离子通道的内源性激动剂。
