Mitragynine, bioactive alkaloid of kratom, reduces chemotherapy-induced neuropathic pain in rats through α-adrenoceptor mechanism
Mitragynine, bioactive alkaloid of kratom, reduces chemotherapy-induced neuropathic pain in rats through α-adrenoceptor mechanism
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DOI：
10.1016/j.drugalcdep.2020.107946
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发表时间：
2020-04-01
影响因子：
4.2
通讯作者：
Rawls, Scott M.
中科院分区：
文献类型：
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作者：
Foss, Jeffery D.;Nayak, Sunil U.;Rawls, Scott M.
背景和目的：卡痛是一种类似咖啡的植物，含有引起阿片类药物和兴奋剂作用的化合物。卡痛叶最常见的生物活性生物碱是帽柱木碱 (MG)。 MG 的阿片类药物作用是显而易见的（例如，镇痛作用以及对 mu、kappa 和 delta 阿片受体的纳摩尔亲和力），但与其他系统（例如肾上腺素能和多巴胺能）相互作用的作用仍不清楚。鉴于增强肾上腺素能传递是大多数一线神经性疼痛药物的常见机制，我们测试了 MG 通过涉及 α-肾上腺素受体激活的机制减轻化疗引起的神经性疼痛的假设。方法：给大鼠注射一次奥沙利铂（6 mg/kg IP）以诱导异常性疼痛，然后用 MG（0、1、5、10 mg/kg IP）治疗 5-7 天。为了研究受体机制，将固定剂量的 MG (5 mg/kg IP) 与育亨宾 (5 mg/kg IP，α(2)-肾上腺素受体拮抗剂)、哌唑嗪 (5 mg/kg IP，α(1)-肾上腺素受体拮抗剂) 或纳曲酮 (5 mg/kg IP，阿片类拮抗剂) 一起注射。 主要结果：MG (5、10 mg/kg) 剂量依赖性降低机械敏感性注射奥沙利铂的大鼠。育亨宾完全抑制 MG 的抗异常性疼痛作用，哌唑嗪和纳曲酮显着降低其作用。 MG 产生适度的过度运动，但剂量 (30 mg/kg) 高于减少异常性疼痛所需的剂量。结论和含义：MG 通过需要活性 α-肾上腺素受体的机制减轻神经性疼痛的发现表明，MG 的药理学特征包括激活肾上腺素能系统以及阿片类药物系统。
Background and Purpose: Kratom is a coffee-like plant containing compounds that cause opioid and stimulant effects. The most prevalent bioactive alkaloid of kratom is mitragynine (MG). Opioid effects of MG are apparent (e.g. antinociception and nanomolar affinity for mu, kappa and delta opioid receptors), but effects encompassing interactions with additional systems, such as adrenergic and dopaminergic, remain undefined. Given that enhanced adrenergic transmission is a mechanism common to most first-line neuropathic pain medications, we tested the hypothesis that MG reduces chemotherapy-induced neuropathic pain through a mechanism involving a-adrenoceptor activation.Methods: Rats were injected once with oxaliplatin (6 mg/kg IP) to induce allodynia and then treated with MG (0, 1, 5, 10 mg/kg IP) for 5-7 days. To investigate receptor mechanisms, a fixed dose of MG (5 mg/kg IP) was injected with yohimbine (5 mg/kg IP, alpha(2)-adrenoceptor antagonist), prazosin (5 mg/kg IP, alpha(1)-adrenoceptor antagonist), or naltrexone (5 mg/kg IP, opioid antagonist).Key Results: MG (5, 10 mg/kg) dose-dependently reduced mechanical sensitivity in oxaliplatin-injected rats. Anti-allodynic effects of MG were completely inhibited by yohimbine, and significantly reduced by prazosin and naltrexone. MG produced modest hyperlocomotion but only at a dose (30 mg/kg) higher than those required to reduce allodynia.Conclusion and Implication: The finding that MG reduced neuropathic pain through a mechanism requiring active alpha-adrenoceptors indicates that the pharmacological profile of MG includes activation of adrenergic, as well as opioid, systems.