Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling.
Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling.
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DOI：
10.1016/j.bbi.2013.06.004
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发表时间：
2013-10
影响因子：
15.1
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
--
作者：
Loram, Lisa C.;Taylor, Frederick R.;Strand, Keith A.;Harrison, Jacqueline A.;RzasaLynn, Rachael;Sholar, Paige;Rieger, Jayson;Maier, Steven F.;Watkins, Linda R.
先前报道了单次鞘内注射腺苷2A受体（A2 AR）激动剂在神经性疼痛的慢性压迫性损伤（CCI）模型中产生异常性疼痛的多周逆转。我们的目的是确定这种长期逆转是否是由A2 AR激动诱导的，而不是更广泛的腺苷受体亚型，并开始探索所涉及的细胞内信号级联。此外，我们试图确定持久的效果是否可以扩展到其他模型的神经性疼痛。我们在CCI中测试了A1 R和A2 BR激动剂，发现A2 BR具有相同的长期效应，但A1 R激动剂没有。A2 AR激动剂（ATL 313）对长期建立的CCI（手术后6周给药）、脊神经结扎和坐骨神经炎性神经病变诱导的机械性异常性疼痛产生显著的长期逆转。为了确定ATL 313是否对神经胶质细胞具有直接作用，将ATL 313与脂多糖在体外共同施用于新生儿小神经胶质细胞和星形胶质细胞。ATL 313显著减弱小胶质细胞和星形胶质细胞中TNFα的产生，但对LPS诱导的IL-10无影响。蛋白激酶C显着逆转了ATL 313在体外对小胶质细胞和星形胶质细胞中TNF的影响，而蛋白激酶A抑制剂只影响小胶质细胞。鞘内PKA和PKC抑制剂均显著逆转A2 AR激动剂对神经性异常性疼痛的作用。因此，IT给药的A2 AR激动剂仍然是治疗神经性疼痛的令人兴奋的新靶点。
A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 wk after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNF in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.
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DOI：
10.1016/0006-291x(90)91544-3
发表时间：
1990-11-15
影响因子：
3.1
作者：
HERBERT, JM;AUGEREAU, JM;MAFFRAND, JP
通讯作者：
MAFFRAND, JP
影响因子：
6.7
作者：
Fredholm, Bertil B.;Chern, Yijuang;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail
DOI：
10.1523/jneurosci.4569-09.2009
发表时间：
2009-11-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Costigan M;Moss A;Latremoliere A;Johnston C;Verma-Gandhu M;Herbert TA;Barrett L;Brenner GJ;Vardeh D;Woolf CJ;Fitzgerald M
通讯作者：
Fitzgerald M
影响因子：
3.3
作者：
Hutchinson, M. R.;Loram, L. C.;Zhang, Y.;Shridhar, M.;Rezvani, N.;Berkelhammer, D.;Phipps, S.;Foster, P. S.;Landgraf, K.;Falke, J. J.;Rice, K. C.;Maier, S. F.;Yin, H.;Watkins, L. R.
通讯作者：
Watkins, L. R.
影响因子：
20.3
作者：
Csoka, Balazs;Nemeth, Zoltan H.;Hasko, Gyorgy
通讯作者：
Hasko, Gyorgy