Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain
Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain
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DOI：
10.1016/s0304-3959(98)00193-6
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发表时间：
1999-03-01
期刊：
影响因子：
7.4
通讯作者：
Eisenach, JC
中科院分区：
文献类型：
--
作者：
Lavand'homme, PM;Eisenach, JC
腺苷类似物在正常动物中产生镇痛作用，并减少脊髓注射后炎症和神经损伤后的异常性疼痛和痛觉过敏，但尚未测试其临床安全性。虽然腺苷本身正处于脊髓给药的临床试验中，但关于腺苷在动物模型中对脊髓的影响的数据很少。在这项研究中，我们确定脊髓给予腺苷可在脊髓神经结扎后大鼠的触觉异常性疼痛中产生剂量依赖性的减少，而不产生运动阻滞。尽管腺苷的最大效果小于 50% 的异常性疼痛逆转，但单次脊髓注射后其作用持续时间>24 小时。相比之下，注射合成腺苷类似物会产生类似程度的抗异常疼痛作用，导致明显的运动阻滞。脊髓阿片类药物的作用被认为部分是由脊髓腺苷释放引起的。我们假设脊髓吗啡在神经损伤引起的异常性疼痛和痛觉过敏中疗效的降低可能反映了这种脊髓阿片-腺苷机制的破坏。脊髓吗啡本身在脊髓神经结扎后对大鼠的异常性疼痛产生了最小程度的减轻，并且脊髓腺苷以相加的方式增强了这种减轻。这种组合的最大效果导致异常性疼痛逆转不到 60%。相比之下，脊髓注射腺苷脱氨酶或再摄取抑制剂大大增强了脊髓吗啡的作用，导致超过 80% 的异常性疼痛逆转。这些结果支持单独使用脊髓腺苷和与吗啡一起治疗神经性疼痛的临床测试，以及在正常和感觉过敏条件下进一步测试所提出的阿片类药物-腺苷联系。 (C) 1999 年国际疼痛研究协会。由 Elsevier Science B.V. 出版
Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions. (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.