Department of Pharmacodynamics, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, 63110, USA.
Cell Mol Neurobiol. 2021 Jul;41(5):1131-1143. doi: 10.1007/s10571-020-01034-7. Epub 2021 Jan 12.
Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.
慢性给予阿片类药物会产生身体依赖性和阿片类药物引起的痛觉过敏。使用者声称，泰国传统茶“咔哇”和成分生物碱育亨宾可改善阿片类药物戒断，而不会增加对疼痛的敏感性。为了验证这些说法，我们评估了咔哇总生物碱提取物（KAE）和两种单体生物碱，即育亨宾（MG）和类似物育亨宾伪吲哚（MP），评估它们在慢性给予后产生身体依赖性和诱导痛觉过敏的能力，以及作为吗啡依赖动物戒断的治疗方法。C57BL/6J 小鼠（每组 10 只）连续给予生理盐水或递增剂量的吗啡（腹腔内；i.p.）、咔哇总生物碱提取物（口服，p.o.）、育亨宾（口服，p.o.）或 MP（皮下，s.c.），共 5 天。用吗啡、KAE 或育亨宾慢性处理的小鼠在第 5 天的 48°C 温水尾巴撤退测试中表现出明显的药物诱导的痛觉过敏。然后，给小鼠注射纳洛酮（10mg/kg，s.c.），并测试阿片类药物戒断症状。咔哇总生物碱提取物和两种单体生物碱表现出的纳洛酮诱发戒断症状明显少于吗啡处理的小鼠。然后，使用另外的 C57BL/6J 小鼠使其对吗啡产生身体依赖性，然后测试联合 KAE、育亨宾或 MP 在接下来的 3 天内每天两次给予的治疗潜力，无论是固定剂量还是逐渐减少的剂量。当给予纳洛酮时，无论是哪种方案治疗的 KAE、育亨宾或 MP 处理的小鼠，与继续接受吗啡的对照小鼠相比，戒断症状明显减少。总之，咔哇、育亨宾和育亨宾伪吲哚在保留一些副作用的情况下，在吗啡依赖动物中产生的身体依赖性明显减少，并改善了阿片类药物戒断，这表明它们具有一定的临床价值。
