Comparison of the ability of adenosine kinase inhibitors and adenosine receptor agonists to attenuate thermal hyperalgesia and reduce motor performance in rats
Comparison of the ability of adenosine kinase inhibitors and adenosine receptor agonists to attenuate thermal hyperalgesia and reduce motor performance in rats
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DOI：
10.1016/s0091-3057(02)00840-7
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发表时间：
2002-10-01
影响因子：
3.6
通讯作者：
McGaraughty, S
中科院分区：
文献类型：
--
作者：
Jarvis, MF;Mikusa, J;McGaraughty, S
腺苷激酶(AK)抑制剂可增加组织过度兴奋部位抑制性神经调节剂腺苷(ADO)的细胞外浓度，并在疼痛和炎症动物模型中产生抗伤害效应。本研究比较了几种新型和选择性的AK抑制剂和ADO受体选择性激动剂减轻角叉菜胶诱导的热痛敏和通过对探索性运动活动和Rotorod性能的影响来损害运动能力的能力。典型的核苷AK抑制剂5‘-脱氧-5-碘-巴马西丁(5’d-5IT)可剂量依赖地阻断热痛觉过敏(ED50=0.2mumol/kg ip)，在降低探索性运动活动和Rotorod性能方面的效力分别降低4倍和75倍。5‘d-5IT的止痛作用可被A(1)拮抗剂环戊基茶碱(CPT)和A(2A)拮抗剂3，7-二甲基-1-炔丙基黄嘌呤(DMPX)完全阻断。新的核苷和非核苷AK抑制剂(A-134974、A-286501和ABT-702)也能有效地阻断角叉菜胶诱导的热痛觉过敏(ED50=0.7-2mumol/kg ip)，其对运动功能的损害作用明显低于5‘d-5IT。全身应用A(1)受体选择性激动剂N-6-环戊基腺苷(CPA)、A(2A)受体选择性激动剂CGS 21680和非选择性ADO受体激动剂N-6-乙基羧胺基腺苷(N-6-ECCA)可有效降低(ED50=0.3~1.0mumol/kg ip)热痛敏。然而，与AK抑制剂不同的是，这些ADO受体激动剂只有在同时降低运动能力的剂量下才能产生显著的抗伤害作用。这些数据表明，与ADO受体激动剂相比，AK抑制剂通过与ADO A(1)和A(2A)受体相互作用产生特定的抗痛觉过敏效应，这种剂量对探索性运动活动和ROTROD性能没有可检测到的影响，并改善了抗伤害效应和运动损伤效应之间的分离。(C)2002 Elsevier Science Inc.保留所有权利。
Inhibitors of adenosine kinase (AK) enhance extracellular concentrations of the inhibitory neuromodulator adenosine (ADO) at sites of tissue hyperexcitability and produce antinociceptive effects in animal models of pain and inflammation. The present study compared the ability of several novel and selective AK inhibitors and ADO receptor-selective agonists to attenuate carrageenan-induced thermal hyperalgesia and to impair motor performance as measured by effects on exploratory motor activity and rotorod performance. The prototypical nucleoside AK inhibitor, 5'deoxy-5-iodotabercidin (5'd-5IT), dose-dependently blocked thermal hyperalgesia (ED50 = 0.2 mumol/kg ip) and was 4- and 75-fold less potent in reducing exploratory motor activity and rotorod performance, respectively. The antihyperalgesic effects of 5'd-5IT were fully blocked by the A(1) antagonist, cyclopentyltheophylline (CPT) and the A(2A) antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). Novel nucleoside and non-nucleoside AK inhibitors (A-134974, A-286501 and ABT-702) also potently (ED50 = 0.7-2 mumol/kg ip) blocked carrageenan-induced thermal hyperalgesia and were significantly less potent than 5'd-5IT in impairing motor performance. The systemic administration of N-6-cyclopentyladenosine (CPA), an A(1) receptor-selective agonist, CGS 21680, an A(2A) receptor-selective agonist, and N-6-ethylcarboxamidoadenosine (NECA), a nonselective ADO receptor agonist potently reduced (ED50 = 0.3-1.0 mumol/kg ip) thermal hyperalgesia. Unlike the AK inhibitors, however, these ADO receptor agonists produced significant antinociception only at doses that also decreased motor performance. These data demonstrate that AK inhibitors produce specific antihyperalgesic effects via an interaction with ADO A(1) and A(2A) receptors at doses that lack detectable effects on exploratory motor activity and rotorod performance and offer an improved separation between antinociceptive and motor impairing effects as compared to ADO receptor agonists. (C) 2002 Elsevier Science Inc. All rights reserved.