Neuropathic Pain and Translational Medicine Research Laboratory, Cathay Medical Research Institute, Cathay General Hospital, Xizhi, New Taipei City, Taiwan.
Life Sci. 2012 Sep 4;91(5-6):213-20. doi: 10.1016/j.lfs.2012.07.005. Epub 2012 Jul 20.
Ultra-low dose naloxone has been shown to restore the antinociceptive effect of morphine in pertussis toxin (PTX)-treated rats by suppressing spinal microglia activation and inhibiting inflammatory cytokine expression. This study was further investigated the mechanism by which ultra-low dose naloxone promotes analgesia in pertussis toxin-treated rats.
Male Wistar rats were implanted with an intrathecal (i.t.) catheter and injected either saline or PTX (1 μg). Four days later, rats randomly received either saline, or ultra-low dose naloxone, or recombinant rat interleukin-10 (rrIL-10) (1 μg) injection followed by saline or morphine (10 μg) 30 min later. In some experiments, mouse anti-rat IL-10 antibody (10 μg) was injected intrathecally into PTX injected rats daily on days 4, 5, 6, and 7. On day 7, ultra-low dose naloxone was given 1h after antibody injection with or without subsequent morphine injection.
PTX injection induced notable thermal hyperalgesia and mechanical allodynia. Injection of ultra-low dose naloxone preserved the antinociceptive effect of morphine in PTX-treated rats and associated an increasing of IL-10 protein expression. Intrathecal injection rrIL-10 alone or in combination with morphine, not only reversed mechanical allodynia but also partially restored the antinociceptive effect of morphine; injection of anti-rat IL-10 antibody attenuated the effect of morphine plus ultra-low dose naloxone on mechanical allodynia and completely inhibited the antinociceptive effect of morphine.
These results indicate that intrathecal ultra-low dose naloxone induces IL-10 expression in spinal neuron and microglia, which suppresses PTX-induced neuroinflammation and restores the antinociceptive effect of morphine.
低剂量纳洛酮已被证明可通过抑制脊髓小胶质细胞激活和抑制炎症细胞因子表达来恢复博莱霉素（PTX）处理大鼠的吗啡镇痛作用。本研究进一步探讨了超低剂量纳洛酮促进博莱霉素处理大鼠镇痛的机制。
雄性 Wistar 大鼠植入鞘内置管，注射生理盐水或博莱霉素（1μg）。4 天后，大鼠随机接受生理盐水、超低剂量纳洛酮或重组大鼠白细胞介素-10（rrIL-10）（1μg）注射，30 分钟后再给予生理盐水或吗啡（10μg）。在一些实验中，每天在博莱霉素注射后第 4、5、6 和 7 天鞘内注射抗鼠白细胞介素-10 抗体（10μg）。第 7 天，在抗体注射后 1 小时给予超低剂量纳洛酮，随后是否给予吗啡注射。
博莱霉素注射引起明显的热痛觉过敏和机械性痛觉过敏。注射超低剂量纳洛酮可维持博莱霉素处理大鼠吗啡的镇痛作用，并伴有白细胞介素-10 蛋白表达增加。鞘内注射 rrIL-10 单独或与吗啡联合应用不仅逆转了机械性痛觉过敏，而且部分恢复了吗啡的镇痛作用；注射抗鼠白细胞介素-10 抗体减弱了吗啡加超低剂量纳洛酮对机械性痛觉过敏的作用，并完全抑制了吗啡的镇痛作用。
这些结果表明，鞘内超低剂量纳洛酮诱导脊髓神经元和小胶质细胞中白细胞介素-10 的表达，抑制博莱霉素诱导的神经炎症，恢复吗啡的镇痛作用。
