Katz N K, Ryals J M, Wright D E
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
Neuroscience. 2015 Jan 29;285:312-23. doi: 10.1016/j.neuroscience.2014.10.065. Epub 2014 Nov 8.
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, N(6)-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.
糖尿病性周围神经病变是糖尿病的常见并发症，相当一部分患者遭受使人衰弱的疼痛，这严重影响了他们的生活质量。不幸的是，对症治疗方法疗效有限，且常常伴有显著的全身不良反应风险。镇痛小分子腺苷激活腺苷A1受体（A1R）已被证明在炎症性和神经性疼痛模型中具有抗伤害感受作用。本研究使用疼痛性糖尿病性神经病变小鼠模型来确定糖尿病对内源性腺苷生成的影响，以及腺苷受体激动剂的中枢或外周给药是否能减轻糖尿病小鼠的机械性异常性疼痛症状。使用链脲佐菌素诱导雄性A/J小鼠患糖尿病。每周测量机械性撤足阈值以表征神经病变表型。在糖尿病诱导后8周，测定背根神经节（DRG）和脊髓中核苷酸外切酶将AMP水解为腺苷的情况。将AMP、腺苷和特异性A1R激动剂N(6)-环戊基腺苷（CPA）分别进行中枢（鞘内）和外周（足底内）给药，以确定腺苷受体激活对糖尿病小鼠机械性异常性疼痛的影响。诱导后8周，糖尿病小鼠DRG中细胞外AMP的水解显著减少；与此同时，与非糖尿病对照组相比，糖尿病小鼠的机械性撤足阈值显著降低。中枢给予AMP、腺苷和CPA可显著提高糖尿病小鼠的机械性撤足阈值。令人惊讶的是，外周给予CPA也可改善糖尿病小鼠的机械性异常性疼痛。本研究提供了新的证据，表明糖尿病显著影响内源性AMP水解，提示腺苷生成改变可能促成疼痛性糖尿病性神经病变的发生。此外，A1R的中枢和外周激活均显著改善了机械性敏感性，有必要进一步研究这一重要的抗伤害感受途径，作为治疗疼痛性糖尿病性神经病变的一种新的治疗选择。
