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Analysis of peripheral mechanism for cold-induced aggravation of pain in inflammation and nerve injury models

炎症及神经损伤模型寒冷致疼痛加剧的外周机制分析

基本信息

批准号：
15390070
负责人：
MIZUMURA Kazue
金额：
$ 9.73万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

To clarify the peripheral mechanism for cold-induced aggravation of pain in inflammation and nerve injury models, following experiments were carried out.1) We examined cold sensitivity of cultured dorsal root ganglion (DRG) neurons obtained from adjuvant-monoarthritic rats using Ca-imaging technique. The percentage of neurons responding to cold down to 10℃ was about 80% both in normal and inflamed animals. Percentage of neurons sensitive to mustard oil (MO, a TRPA1 agonist) was 56% in inflamed animals, much higher than 20% in normal group. The great majority of neurons sensitive to menthol (MT, a TRPM8 agonist) was also sensitive to MO. The threshold temperature to cooling of MO-sensitive and MT-insensitive neurons was 18.4℃ in inflamed group, higher than 14.0℃ in the normal group.2) We demonstrated the temperature dependency of acid sensitivity in cultured DRG neurons.3) Mechanical hyperalgesia in adjuvant-monoarthritic rats was worsened by exposure to cold (15℃).4) To know the basic mechanism for inflammatory hyperalgesia, we examined effects of ATP on C-fiber receptors. ATP suppressed through P2X receptors the heat response of nociceptors at a low concentration (10μM), while it facilitated the heat response through P2Y receptors at a high concentration (1mM).5) To clarify the interaction of various inflammatory mediators, we examined effects of bradykinin (BK) and noradrenaline (NA) on single C-fiber receptor activities. BK-induced discharges were enhanced by pretreatment with NA, vice versa. This result suggests that despite of its weak excitatory effect by itself, NA in co-operation with other mediators induces larger effects.6) We induced muscle mechanical hyperalgesia by lengthening contraction of the dorsi-flexors of the lower hindpaw. We demonstrated that the mechanical sensitivity of muscle C-fiber receptors was increased in this hyperalgesic muscle.

为了阐明冷刺激加重炎症和神经损伤模型疼痛的外周机制，本研究进行了以下实验：1）采用钙离子成像技术检测了体外培养的单侧关节炎大鼠背根神经节（DRG）神经元的冷敏感性。在正常和炎症的动物中，对冷至10℃反应的神经元的百分比都在80%左右。对芥子油（MO，TRPA 1激动剂）敏感的神经元百分比在炎症动物中为56%，远高于正常组的20%。绝大多数对薄荷醇（MT，TRPM 8激动剂）敏感的神经元也对MO敏感。实验结果表明：（1）培养的DRG神经元对酸的敏感性存在温度依赖性;（2）慢性炎症大鼠的机械性痛觉过敏随着冷暴露（15℃）的增加而加重;（3）为了解炎性痛觉过敏的基本机制，我们检测了ATP对C-纤维受体的影响。低浓度（10μM）ATP通过P2 X受体抑制伤害性感受器的热反应，而高浓度（1 mM）ATP通过P2 Y受体促进伤害性感受器的热反应。5）为了阐明各种炎症介质的相互作用，我们检测了缓激肽（BK）和去甲肾上腺素（NA）对单个C纤维受体活性的影响。BK诱导的放电增强预处理与NA，反之亦然。这一结果表明，尽管其本身的兴奋作用弱，NA与其他介质的合作诱导更大的效果。6）我们诱导肌肉机械性痛觉过敏延长收缩的背屈肌的下后爪。我们证明，肌肉C-纤维受体的机械敏感性增加，在这种痛觉过敏的肌肉。