Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC₀₋₆₀, p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.

细胞色素 P450 2D (CYP2D) 介导了几类精神药物（包括阿片类药物）的激活和失活，这些药物可以改变药物反应。曲马多是一种合成的阿片类药物，具有自身的镇痛活性，并被 CYP2D 代谢激活为 O-去甲基曲马多 (ODMST)，一种阿片受体激动剂。我们研究了大脑 CYP2D 代谢对中枢曲马多和 ODSMT 水平的影响，以及在大鼠口服曲马多后产生的镇痛反应。CYP2D 抑制剂普萘洛尔和普罗帕酮在口服曲马多之前通过脑室内给药，镇痛作用通过甩尾潜伏期测量。使用 LC-ESI-MS/MS 通过微透析评估血浆和脑中曲马多及其代谢物 ODSMT 和 N-去甲基曲马多的药物水平。₀₋₆₀ , p < 0.01)。这种效应与曲马多及其代谢物的脑水平变化有关，与脑 CYP2D 抑制一致。总之，在口服曲马多给药预处理下，中央给药 CYP2D 抑制剂普罗帕酮增加了镇痛作用（不改变血浆药物或代谢物水平），表明曲马多本身（和大脑内 CYP2D 的活性）有助于镇痛。