Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.
Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.
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DOI：
10.1016/j.ejps.2016.03.019
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发表时间：
2016-09
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影响因子：
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通讯作者：
W. Ochiai;M. Kaneta;Marina Nagae;Ami Yuzuhara;Xin Li;Haruka Suzuki;Mika Hanagata;S. Kitaoka;Wataru Suto;Yoshiki Kusunoki;R. Kon;Kazuhiko Miyashita;D. Masukawa;N. Ikarashi;M. Narita;Tsutomu Suzuki;K. Sugiyama
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文献类型：
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作者：
W. Ochiai;M. Kaneta;Marina Nagae;Ami Yuzuhara;Xin Li;Haruka Suzuki;Mika Hanagata;S. Kitaoka;Wataru Suto;Yoshiki Kusunoki;R. Kon;Kazuhiko Miyashita;D. Masukawa;N. Ikarashi;M. Narita;Tsutomu Suzuki;K. Sugiyama
神经性疼痛患者长期服用吗啡会导致对吗啡逐渐产生耐受性。虽然这种作用的详细机制尚未阐明，但已知的原因之一是中脑腹被区中吗啡活性代谢物 M-6-G（吗啡-6-葡萄糖醛酸）的 μ-阿片受体功能下降。在这项研究中，研究了在存在神经性疼痛的情况下给予吗啡后大脑中吗啡的浓度与其镇痛效果之间的关系。给患有神经性疼痛的小鼠口服吗啡，分析吗啡的镇痛效果与其在大脑中的浓度之间的关系。此外，还检测了以吗啡为底物的结合酶 UGT2B（尿苷二磷酸葡萄糖醛酸基转移酶）和参与吗啡排泄的转运蛋白 P-gp 的表达水平。在患有神经性疼痛的小鼠中，大脑中吗啡的浓度显着降低，并且发现这种降低与镇痛效果的降低之间存在相关性。人们认为脑内吗啡浓度的降低可能是由于小肠中P-gp表达水平的增加以及肝脏中UGT2B表达水平和结合活性的增加所致。本研究的结果表明，在存在神经性疼痛的情况下给予吗啡时，由于到达大脑的吗啡和M-6-G的总量减少，可能无法获得足够的镇痛效果。
The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain.