Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat.
Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat.
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DOI：
10.1016/j.physbeh.2017.11.030
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发表时间：
2018-04-01
影响因子：
2.9
通讯作者：
Murphy AZ
中科院分区：
文献类型：
--
作者：
Doyle HH;Murphy AZ
临床前研究报告，吗啡在女性中的有效剂量大约是男性的2倍。全身给药后，吗啡在肝脏和大脑中通过II期葡萄糖醛酸化代谢为两种活性代谢物：吗啡-3-葡萄糖醛酸盐（M3G）和吗啡-6-葡萄糖醛酸盐（M6G），它们各自具有不同的药理特征。M6G与μ阿片受体结合，作为一种有效的镇痛药。相反，M3G与toll样受体4 （TLR4）结合，引发神经炎症反应，直接对抗吗啡和M6G的镇痛作用。女性的M3G血清浓度比男性高2倍，然而，吗啡代谢物对体内镇痛和神经胶质活化的性别特异性影响尚不清楚。目前的研究验证了M3G的增加以及随后tlr4介导的胶质细胞激活是导致雌性吗啡反应减弱的主要机制的假设。我们证明pag内M6G在女性中比单独使用吗啡产生更大的镇痛反应。（−）-纳洛酮可逆转M6G镇痛，但(+)-纳洛酮不能逆转M6G镇痛，提示这种作用是μ阿片受体介导的。相比之下，pag内注射M3G显著减弱了全身吗啡的镇痛作用，使吗啡的有效剂量增加了两倍（5.0 vs 10.3 mg/kg），消除了先前观察到的性别差异。在pag内注射吗啡或M6G后，雌鼠IL-1β、IL-6和TNF均升高。在男性中，服用吗啡后只有IL-1β水平升高。在女性中，M3G后细胞因子水平的变化仅限于TNF。总之，这些数据暗示了吗啡代谢的性别差异，特别是M3G，是女性对吗啡反应减弱的一个因素。
Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is metabolized via Phase II glucuronidation in the liver and brain into two active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), each possessing distinct pharmacological profiles. M6G binds to μ opioid receptors and acts as a potent analgesic. In contrast, M3G binds to toll-like receptor 4 (TLR4), initiating a neuroinflammatory response that directly opposes the analgesic effects of morphine and M6G. M3G serum concentrations are 2-fold higher in females than males, however, sex-specific effects of morphine metabolites on analgesia and glial activation in vivo remain unknown. The present studies test the hypothesis that increased M3G, and subsequent TLR4-mediated activation of glia, is a primary mechanism driving the attenuated response to morphine in females. We demonstrate that intra-PAG M6G results in a greater analgesic response in females than morphine alone. M6G analgesia was reversed with co-administration of (−)-naloxone, but not (+)-naloxone, suggesting that this effect is μ opioid receptor mediated. In contrast, intra-PAG administration of M3G significantly attenuated the analgesic effects of systemic morphine in males only, increasing the 50% effective dose of morphine two-fold (5.0 vs 10.3 mg/kg) and eliminating the previously observed sex difference. An increase in IL-1β, IL-6 and TNF was observed in females following intra-PAG morphine or M6G. In males, only IL-1β levels increased following morphine. Changes in cytokine levels following M3G were limited to TNF in females. Together, these data implicate sex differences in morphine metabolism, specifically M3G, as a contributing factor in the attenuated response to morphine observed in females.
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影响因子：
2.7
作者：
Bernal, Scott A.;Morgan, Michael M.;Craft, Rebecca M.
通讯作者：
Craft, Rebecca M.
影响因子：
7.6
作者：
Eidson, Lori N.;Inoue, Kiyoshi;Murphy, Anne Z.
通讯作者：
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影响因子：
2.9
作者：
DAWSONBASOA, MB;GINTZLER, AR
通讯作者：
GINTZLER, AR
影响因子：
2.1
作者：
EKBLOM, M;GARDMARK, M;HAMMARLUNDUDENAES, M
通讯作者：
HAMMARLUNDUDENAES, M
影响因子：
10.7
作者：
Cann, C;Curran, J;Ho, B
通讯作者：
Ho, B