REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; Molecular Oncology GRP and Virology LB, Portuguese Institute of Oncology-Porto, Porto, Portugal; IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences - North, (ISCS-N), CESPU, CRL, Gandra Portugal.
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal; IBMC - Institute of Molecular and Cell Biology, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
Life Sci. 2014 Jul 30;109(2):104-10. doi: 10.1016/j.lfs.2014.06.010. Epub 2014 Jun 24.
Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles, interindividual variability and co-administration of drugs that interfere with metabolism may affect analgesia. The aim of the study was to investigate the repercussions of administration of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using the Guinea pig as a suitable model.
Thirty male Dunkin-Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine+morphine, TCDD and TCDD+morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35-52.5°C), during 60min after morphine administration. Then, blood was collected and plasma morphine and metabolites were quantified.
Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature of 52.5°C, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p<0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p<0.001 and p<0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.
Our results indicate that modulation of morphine metabolism may result in variations in metabolite concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to improve morphine effect in clinical practice.
吗啡广泛代谢为神经毒性的吗啡-3-葡糖苷酸（M3G）和阿片类激动剂吗啡-6-葡糖苷酸（M6G）。由于这些不同的作用，个体间的差异和共同给予干扰代谢的药物可能会影响镇痛作用。本研究旨在探讨葡糖苷酸化诱导剂（2,3,7,8-四氯二苯并-p-二恶英，TCDD）和抑制剂（雷尼替丁）对吗啡代谢和随后镇痛作用的影响，使用豚鼠作为合适的模型。
将 30 只雄性 Dunkin-Hartley 豚鼠分为六组：对照组、吗啡组、雷尼替丁组、雷尼替丁+吗啡组、TCDD 组和 TCDD+吗啡组。在先前暴露于 TCDD 和雷尼替丁后，通过增加温度热板（35-52.5°C）评估吗啡作用，在给予吗啡后 60 分钟内进行。然后，采集血液并定量血浆吗啡和代谢物。
与吗啡组相比，用 TCDD 处理的动物表现出更快的镇痛作用，75%的动物达到 52.5°C 的截止温度，而吗啡组只有 25%的动物达到该温度。与吗啡组相比，用雷尼替丁处理的动物表现出明显较低的镇痛作用（p<0.05）。此外，各组之间在 M3G 水平和 M3G/吗啡比值方面存在显著差异（p<0.001 和 p<0.0001），TCDD 动物的 M3G、M6G、M3G/吗啡和 M6G/吗啡值最高，而吗啡值最低。用雷尼替丁处理的动物则相反。
我们的结果表明，吗啡代谢的调节可能导致代谢物浓度的变化，从而导致对吗啡的不同镇痛反应，在一种可能用于改善临床实践中吗啡作用的动物模型中。
