Nicotine Increases Codeine Analgesia Through the Induction of Brain CYP2D and Central Activation of Codeine to Morphine
Nicotine Increases Codeine Analgesia Through the Induction of Brain CYP2D and Central Activation of Codeine to Morphine
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DOI：
10.1038/npp.2015.32
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发表时间：
2015-06-01
影响因子：
7.6
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
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作者：
McMillan, Douglas M.;Tyndale, Rachel F.
CYP 2D将可待因代谢活化为吗啡，这是可待因镇痛所需的。通过血脑屏障的渗透性和主动外排表明，可待因后脑中的初始吗啡是由于脑CYP 2D代谢。吸烟者大脑中的人CYP 2D较高，但肝脏中的人CYP 2D不高，7天尼古丁处理诱导大鼠大脑中的CYP 2D，但不诱导肝脏中的CYP 2D。尼古丁诱导的大鼠脑CYP 2D在外周给药可待因的中枢代谢活化和镇痛中的作用进行了研究。大鼠接受为期7天的尼古丁（1 mg/kg皮下注射）和/或普萘洛尔（基于CYP 2D机制的抑制剂; 20 μ g脑室内注射）预处理，然后检测可待因（20 mg/kg腹腔注射）或吗啡（3.5 mg/kg腹腔注射）后的镇痛和药物水平，与镇痛峰值匹配。尼古丁增加可待因镇痛（1.59倍AUC（0-30 min）vs溶媒; p
CYP2D metabolically activates codeine to morphine, which is required for codeine analgesia. Permeability across the blood-brain barrier, and active efflux, suggests that initial morphine in the brain after codeine is due to brain CYP2D metabolism. Human CYP2D is higher in the brains, but not in the livers, of smokers and 7-day nicotine treatment induces rat brain, but not hepatic, CYP2D. The role of nicotine-induced rat brain CYP2D in the central metabolic activation of peripherally administered codeine and resulting analgesia was investigated. Rats received 7-day nicotine (1 mg/kg subcutaneously) and/or a single propranolol (CYP2D mechanism-based inhibitor; 20 mu g intracerebroventricularly) pretreatment, and then were tested for analgesia and drug levels following codeine (20 mg/kg intraperitoneally) or morphine (3.5 mg/kg intraperitoneally), matched for peak analgesia. Nicotine increased codeine analgesia (1.59X AUC(0-30 min) vs vehicle; p