Mu-opioid and noradrenergic α2-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats
Mu-opioid and noradrenergic α2-adrenoceptor contributions to the effects of tapentadol on spinal electrophysiological measures of nociception in nerve-injured rats
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DOI：
10.1016/j.pain.2010.10.004
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发表时间：
2011-01-01
期刊：
影响因子：
7.4
通讯作者：
Dickenson, Anthony H.
中科院分区：
文献类型：
--
作者：
Bee, Lucy A.;Bannister, Kirsty;Dickenson, Anthony H.
多个感觉部位的多种病理机制可能是神经损伤后疼痛的根源。这为推荐一种以上药物（顺序或组合）进行治疗提供了基础。根据这一前提，在单个分子中结合不同镇痛作用机制的新药正在获得发展动力，例如他喷他多刺激μ阿片受体（MOR）并在中枢神经系统中充当去甲肾上腺素再摄取抑制剂（NRI）。他喷他多目前适用于治疗中度至重度急性和重度慢性疼痛，在这里我们证明了其在持续神经性疼痛动物模型中的功效。特别是，我们在脊髓神经结扎和假手术大鼠中进行了一系列体内电生理学测试，结果表明全身他喷他多（1 和 5 mg/kg）剂量依赖性地降低了脊髓背角神经元对一系列外周刺激（包括刷子、点状机械和热刺激）的诱发反应。此外，我们还发现，选择性α（2）-肾上腺素受体拮抗剂阿替美唑或μ阿片受体拮抗剂纳洛酮的脊髓应用几乎完全逆转了他喷他多的抑制作用，这表明不仅脊髓是他喷他多作用的关键部位，而且表明除了MOR-NRI之外，没有其他药理学参与其镇痛。此外，根据拮抗剂在假手术和SNL大鼠中逆转他喷他多抑制的程度，我们认为可能从对照动物中主要的阿片类抑制机制转变为神经病动物中主要的去甲肾上腺素能抑制机制。 (C) 2010 年国际疼痛研究协会。由 Elsevier B.V. 出版。保留所有权利。
Multiple pathological mechanisms at multiple sensory sites may underlie the pain that follows nerve injury. This provides a basis for recommending more than one agent, either sequentially or in combination, for its treatment. According to this premise, new drugs that combine different mechanisms of analgesic action in a single molecule are gaining momentum, such as tapentadol which stimulates mu-opioid receptors (MOR) and acts as a noradrenaline reuptake inhibitor (NRI) in the CNS. Tapentadol is currently indicated for treating moderate to severe acute and severe chronic pain, and here we demonstrate its efficacy in an animal model of ongoing neuropathic pain. In particular, we performed a series of in vivo electrophysiological tests in spinal nerve ligated and sham-operated rats to show that systemic tapentadol (1 and 5 mg/kg) dose-dependently reduced evoked responses of spinal dorsal horn neurones to a range of peripheral stimuli, including brush, punctate mechanical and thermal stimuli. Furthermore, we showed that spinal application of the selective alpha(2)-adrenoceptor antagonist atipamezole, or alternatively the mu-opioid receptor antagonist naloxone, produced near complete reversal of tapentadol's inhibitory effects, which suggests not only that the spinal cord is the key site of tapentadol's actions, but also that no pharmacology other than MOR-NRI is involved in its analgesia. Moreover, according to the extent that the antagonists reversed tapentadol's inhibitions in sham and SNL rats, we suggest that there may be a shift from predominant opioid inhibitory mechanisms in control animals, to predominant noradrenergic inhibition in neuropathic animals. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.