Analgesic tolerance to morphine is regulated by PPARγ
Analgesic tolerance to morphine is regulated by PPARγ
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DOI：
10.1111/bph.12851
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发表时间：
2014-12-01
影响因子：
7.3
通讯作者：
Ciccocioppo, Roberto
中科院分区：
文献类型：
--
作者：
de Guglielmo, Giordano;Kallupi, Marsida;Ciccocioppo, Roberto
背景与目的阿片类药物是强效镇痛药。然而，长期使用这些药物会导致对其镇痛作用的耐受性迅速发展，并随之增加显著的副作用，包括药物依赖和成瘾。实验方法采用小鼠尾部浸泡法，隔日监测小鼠热痛耐受性的变化。关键结果吗啡（30 mg/kg，bid）每日一次给药可使小鼠热痛耐受性迅速形成。吡格列酮（10和30 mg/kg，bid）联合给药可显著减弱耐受的形成和表达。预先给予选择性PPAR拮抗剂GW-9662（5 mg/kg，bid）可完全阻断这种作用。注射GW-9662和低剂量吗啡（15 mg/kg，bid）可加速耐受的形成。随后，我们发现，条件性神经元过氧化物酶体增殖物激活受体敲除（KO）小鼠开发一个更快速和明显的耐受吗啡镇痛相比，野生型（WT）控制。此外，在PPAR基因敲除小鼠，吡格列酮不再能够防止发展的吗啡tolerance.Conclusions和影响总体而言，我们的研究结果表明，PPAR起着滋补作用的调制吗啡耐受性，其药理学激活可能有助于减少其发展。这些发现提供了关于神经元PPAR的作用的新信息，并表明将PPAR激动剂与阿片类镇痛剂结合可能会减少耐受性的发展，并可能减弱阿片类药物滥用的可能性。
Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPAR in the development of analgesic tolerance to morphine in mice.Experimental Approach We monitored analgesia on alternate days using the tail immersion test.Key Results Daily administration of morphine (30mgkg(-1), bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30mgkg(-1), bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5mgkg(-1), bid), a selective PPAR antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15mgkg(-1), bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPAR knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPAR KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance.Conclusions and Implications Overall, our results demonstrate that PPAR plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPAR and suggest that combining PPAR agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.