Tolerance to the antinociceptive and hypothermic effects of morphine is mediated by multiple isoforms of c-Jun N-terminal kinase
Tolerance to the antinociceptive and hypothermic effects of morphine is mediated by multiple isoforms of c-Jun N-terminal kinase
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DOI：
10.1097/wnr.0000000000000551
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发表时间：
2016-04-13
期刊：
影响因子：
1.7
通讯作者：
Morgan, Daniel J.
中科院分区：
文献类型：
--
作者：
Yuill, Matthew B.;Zee, Michael L.;Morgan, Daniel J.
阿片类药物的滥用和过量是全球日益严重的公共卫生问题。虽然在了解阿片类药物耐受性的机制方面取得了进展，但涉及的确切细胞机制仍不清楚。然而，越来越多的证据表明，c-Jun N-末端激酶（JNK）在μ阿片受体调节和吗啡耐受中发挥重要作用。在这项研究中，我们的目的是确定不同的JNK亚型的耐受性的发展中的潜在作用，吗啡的抗伤害性和低温效应。我们使用热板和甩尾试验来测量对每日一次皮下注射10 mg/kg吗啡的镇痛作用的耐受性。还测量体温以确定对吗啡的低温效应的耐受性。在野生型小鼠中评估对吗啡的耐受性，并与缺乏JNK同种型（JNK 1、JNK 2或JNK 3）的单敲除小鼠进行比较。我们发现，每一个人的JNK亚型的损失会导致损害耐受性的抗伤害和每日吗啡的降温作用。然而，JNK 2的破坏似乎对吗啡耐受性具有最深远的影响。这些结果表明JNK信号通路在吗啡耐受中的明确作用。这补充了先前的研究，表明JNK 2亚型是吗啡耐受所必需的，但另外提出了新的数据，表明额外的JNK亚型也有助于这一过程。
The abuse and overdose of opioid drugs are growing public health problems worldwide. Although progress has been made toward understanding the mechanisms governing tolerance to opioids, the exact cellular machinery involved remains unclear. However, there is growing evidence to suggest that c-Jun N-terminal kinases (JNKs) play a major role in mu-opioid receptor regulation and morphine tolerance. In this study, we aimed to determine the potential roles of different JNK isoforms in the development of tolerance to the antinociceptive and hypothermic effects of morphine. We used the hot-plate and tail-flick tests for thermal pain to measure tolerance to the antinociceptive effects of once-daily subcutaneous injections with 10mg/kg morphine. Body temperature was also measured to determine tolerance to the hypothermic effects of morphine. Tolerance to morphine was assessed in wild-type mice and compared with single knockout mice each lacking the JNK isoforms (JNK1, JNK2, or JNK3). We found that loss of each individual JNK isoform causes impairment in tolerance for the antinociceptive and hypothermic effects of daily morphine. However, disruption of JNK2 seems to have the most profound effect on morphine tolerance. These results indicate a clear role for JNK signaling pathways in morphine tolerance. This complements previous studies suggesting that the JNK2 isoform is required for morphine tolerance, but additionally presents novel data suggesting that additional JNK isoforms also contribute toward this process.