Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy.
Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy.
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DOI：
10.1016/j.neuroscience.2014.10.065
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发表时间：
2015-01-29
期刊：
影响因子：
3.3
通讯作者：
Wright, D. E.
中科院分区：
文献类型：
--
作者：
Katz, N. K.;Ryals, J. M.;Wright, D. E.
糖尿病周围神经病变是糖尿病的一种常见并发症，很大一部分人遭受衰弱性疼痛，严重影响他们的生活质量。不幸的是，对症治疗方案的疗效有限，而且往往有很大的全身不良反应的风险。镇痛小分子腺苷激活腺苷A1受体（A1R）已被证明在炎症和神经性疼痛模型中具有抗伤害性益处。目前的研究使用疼痛性糖尿病神经病变小鼠模型来确定糖尿病对内源性腺苷产生的影响，以及是否中枢或外周递送腺苷受体激动剂可以减轻糖尿病小鼠机械异位性疼痛的迹象。用链脲佐菌素诱导雄性A/J小鼠糖尿病。每周测量机械戒断阈值以表征神经病变表型。在糖尿病诱导后8周，在背根神经节（DRG）和脊髓中测定外核苷酸酶将AMP水解成腺苷的情况。AMP、腺苷和特异性A1R激动剂n6 -环戊基腺苷（CPA）分别在中央（鞘内）和外周（足底内）给药，以确定腺苷受体的激活对糖尿病小鼠机械异位性疼痛的影响。诱导8周后，糖尿病小鼠DRG细胞外AMP水解明显减少；与此同时，与非糖尿病对照组相比，糖尿病小鼠的机械戒断阈值显着降低。中枢给药AMP、腺苷和CPA可显著提高糖尿病小鼠的机械戒断阈值。令人惊讶的是，外周给药CPA也改善了糖尿病小鼠的机械异常性疼痛。该研究提供了新的证据，表明糖尿病显著影响内源性AMP水解，表明腺苷产生的改变可能有助于糖尿病性神经病变的发展。此外，中枢和外周激活A1R显著改善机械敏感性，值得进一步研究这一重要的抗感觉通路作为治疗疼痛性糖尿病神经病变的新治疗选择。
Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8-weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N6-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of painful diabetic neuropathy. Moreover, central and peripheral activation of A1R significantly improved mechanical sensitivity, warranting further investigation into this important antinociceptive pathway as a novel therapeutic option for the treatment of painful diabetic neuropathy.
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DOI：
10.1016/j.jpain.2009.09.008
发表时间：
2010-04
期刊：
The journal of pain
影响因子：
--
作者：
Corder G;Siegel A;Intondi AB;Zhang X;Zadina JE;Taylor BK
通讯作者：
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影响因子：
5.3
作者：
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2012-11-01
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影响因子：
5
作者：
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影响因子：
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作者：
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