Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery
Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery
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DOI：
10.1097/00000542-200703000-00021
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发表时间：
2007-03-01
期刊：
影响因子：
8.8
通讯作者：
Eisenach, James C.
中科院分区：
文献类型：
--
作者：
Hayashida, Ken-ichiro;DeGoes, Sophia;Eisenach, James C.
背景：加巴喷丁已被报道在动物和人类中抑制各种急性和慢性疼痛情况。尽管加巴喷丁的疗效依赖于电压门控性钙通道的α(2)β亚基，但其体内的镇痛机制仍不清楚。在此，作者测试了脊髓去甲肾上腺素抑制在加巴喷丁用于术后镇痛中的作用。方法：在切爪后第二天，给大鼠口服加巴喷丁和脑室注射加巴喷丁，测量大鼠对爪压的戒断阈值。作者还检测了服用安慰剂或加巴喷丁的患者术后脑脊液去甲肾上腺素浓度和术后吗啡使用情况。结果：口服和侧脑室注射加巴喷丁均可剂量依赖性地减轻大鼠术后超敏反应。鞘内注射α(2)-肾上腺素能受体拮抗剂咪唑克生和G蛋白偶联内向整流钾通道拮抗剂Tertiapin-Q可阻断加巴喷丁的这种作用，但不能被阿托品阻断。在人类中，加巴喷丁1200 mg可显著增加脑脊液中去甲肾上腺素的浓度，减少吗啡用量。结论：这些数据提示加巴喷丁激活下行去甲肾上腺素系统，诱导脊髓去甲肾上腺素释放，通过刺激脊髓α(2)肾上腺素受体产生镇痛，随后激活G蛋白偶联的内向整流钾通道。作者的临床数据表明，加巴喷丁在手术前口服后激活去甲肾上腺素下行系统。这些数据支持口服加巴喷丁减轻术后疼痛的中心机制，并表明这种作用可以通过增加去甲肾上腺素释放的治疗来放大。
Background: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the alpha(2)delta subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain.Methods: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin.Results: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the alpha(2)-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. in humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements.Conclusions: These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha(2)-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.