Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain.
Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain.
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DOI：
10.1177/17448069211003375
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发表时间：
2021-01
期刊：
影响因子：
3.3
通讯作者：
Klein AH
中科院分区：
文献类型：
--
作者：
Okerman T;Jurgenson T;Moore M;Klein AH
本文提出的研究旨在确定阿片诱导的耐受性是否与脊髓或周围神经系统中pi3k - γ- akt - cgmp - jnk细胞内信号通路的活性变化有关。雄性C57Bl/6小鼠皮下注射吗啡或生理盐水，每天2次，连续5天（15 mg/kg）。另一组小鼠在吗啡耐受开始前一周接受脊髓神经结扎（SNL）。随后，分离脊髓、背根神经节和坐骨神经，定量测定总磷酸化JNK水平、cGMP水平，并分析Pik3cg、Akt1、Pten和nNos1的基因表达。SNL后，吗啡耐受小鼠和吗啡耐受小鼠脊髓中该通路下调，坐骨神经中表达增加。我们还观察到吗啡耐受小鼠SNL的坐骨神经中磷酸化JNK水平显著增加。用沙利度胺、槲皮素或SP600125对PI3K或JNK进行药理学抑制，通过热脱爪测量，可以减弱SNL小鼠吗啡耐受性的发展。总之，PI3K/AKT细胞内信号通路是降低周围神经系统吗啡耐受发展的潜在靶点。对这一途径的持续研究将有助于开发新的镇痛药物疗法。
Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0914733107
发表时间：
2010-03-02
影响因子：
11.1
作者：
Cunha, Thiago M.;Roman-Campos, Danilo;Ferreira, Sergio H.
通讯作者：
Ferreira, Sergio H.