Rashid Md Harunor, Inoue Makoto, Kondo Saori, Kawashima Toshiko, Bakoshi Shiho, Ueda Hiroshi
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
J Pharmacol Exp Ther. 2003 Mar;304(3):940-8. doi: 10.1124/jpet.102.046250.
Here, we investigated the mechanism of the antihyperalgesic effect of capsaicin cream in the nerve injury-induced neuropathic pain model in mice. In naive mice, application of capsaicin cream onto footpad caused no significant changes in the thermal latency in contrast to the severe thermal hyperalgesia induced by a capsaicin ointment. On the other hand, application of the cream 3 h before test concentration dependently reversed both thermal and mechanical hyperalgesia observed after partial sciatic nerve injury in mice. In algogenic-induced nociceptive flexion (ANF) test, application of 0.1% capsaicin cream in naive mice blocked intraplantar (i.pl.) nociceptin- and ATP-induced flexion responses, whereas prostaglandin I(2) (PGI(2)) agonist-induced responses were unaffected. After nerve injury PGI(2) agonist-induced flexion responses were hypersensitized, and capsaicin cream concentration dependently blocked these hyperalgesic responses. Intraplantar injection of capsaicin solution in ANF test also produced potent flexion responses in naive mice that were lost after neonatal capsaicin-treatment. Partial sciatic nerve injury in neonatal capsaicin-treated mice caused reappearance of i.pl. capsaicin-induced flexion responses, suggesting novel expression of capsaicin receptors due to injury. The PGI(2) agonist-induced responses were also hypersensitized in such injured mice. Capsaicin cream completely reversed both i.pl. capsaicin- or i.pl. PGI(2) agonist-induced hyperalgesia in neonatal capsaicin-treated injured mice. Finally, novel expression of VR1 receptors on neonatal capsaicin-insensitive neurons after nerve injury was confirmed by immunohistochemistry. The newly expressed VR1 receptors after nerve injury were mainly confined to A-fibers. Together, our results suggest that novel expression of capsaicin receptors in neuropathic condition contributes to the analgesic effects of the capsaicin cream.
在此，我们研究了辣椒素乳膏在小鼠神经损伤诱导的神经性疼痛模型中产生抗痛觉过敏作用的机制。在未处理的小鼠中，与辣椒素软膏诱导的严重热痛觉过敏相反，将辣椒素乳膏涂抹于足垫并未引起热潜伏期的显著变化。另一方面，在测试前3小时涂抹该乳膏可浓度依赖性地逆转小鼠坐骨神经部分损伤后观察到的热痛觉过敏和机械性痛觉过敏。在致痛性伤害性屈曲（ANF）试验中，在未处理的小鼠中涂抹0.1%辣椒素乳膏可阻断足底（i.pl.）强啡肽和ATP诱导的屈曲反应，而前列腺素I(2)（PGI(2)）激动剂诱导的反应未受影响。神经损伤后，PGI(2)激动剂诱导的屈曲反应变得超敏，辣椒素乳膏浓度依赖性地阻断这些痛觉过敏反应。在ANF试验中，足底注射辣椒素溶液在未处理的小鼠中也产生了强烈的屈曲反应，而新生小鼠经辣椒素处理后该反应消失。新生小鼠经辣椒素处理后坐骨神经部分损伤导致足底辣椒素诱导的屈曲反应再次出现，提示损伤导致辣椒素受体的新表达。在这种损伤小鼠中，PGI(2)激动剂诱导的反应也变得超敏。辣椒素乳膏完全逆转了新生小鼠经辣椒素处理的损伤小鼠中足底辣椒素或足底PGI(2)激动剂诱导的痛觉过敏。最后，通过免疫组织化学证实了神经损伤后新生小鼠对辣椒素不敏感的神经元上VR1受体的新表达。神经损伤后新表达的VR1受体主要局限于A纤维。总之，我们的结果表明，在神经性疼痛状态下辣椒素受体的新表达有助于辣椒素乳膏的镇痛作用。
