The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy.
The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy.
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发表时间：
1997
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通讯作者：
L. Stone;L. Macmillan;K. F. Kitto;L. Limbird;G. Wilcox
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作者：
L. Stone;L. Macmillan;K. F. Kitto;L. Limbird;G. Wilcox
作用于α 2肾上腺素能受体和阿片受体的激动剂具有镇痛特性，并在脊髓中协同作用；这种协同作用也可能有助于脊髓给药吗啡的效力和疗效。亚型选择性药物的缺乏阻碍了肾上腺素能受体亚型介导这些作用的定义。因此，我们利用表达alpha2a肾上腺素能受体（alpha2aAR）点突变（D79N）的转基因小鼠系来研究alpha2aAR在alpha2激动剂诱发的镇痛和肾上腺素能-阿片协同作用中的作用。在甩尾试验中，鞘内给药UK 14304（一种非亚型选择性alpha2AR激动剂）对D79N小鼠没有镇痛作用，而在本试验中，吗啡（鞘内）的镇痛效力不受突变的影响。该突变还减少了α 2激动剂介导的脊髓镇痛，并阻断了野生型小鼠在P物质行为测试中与δ -阿片激动剂deltorphin II和微阿片激动剂[D-ALA2，N-Me-Phe4， gy -ol5]-脑啡肽（DAMGO）的协同作用。此外，在本试验中，脊髓给药吗啡的效力降低，表明在该模型中，影响α 2aar的降去甲肾上腺素能系统的激活有助于吗啡诱导的脊髓抑制。这些结果表明，α 2aar亚型是α 2肾上腺素能脊髓镇痛的主要介质，并且是与阿片类药物协同镇痛所必需的。因此，针对α 2aar和阿片受体的联合治疗可能有助于在降低总剂量需求的同时最大化阿片样物质的镇痛效果。
Agonists acting at alpha2 adrenergic and opioid receptors have analgesic properties and act synergistically when co-administered in the spinal cord; this synergy may also contribute to the potency and efficacy of spinally administered morphine. The lack of subtype-selective pharmacological agents has previously impeded the definition of the adrenergic receptor subtype(s) mediating these effects. We therefore exploited a genetically modified mouse line expressing a point mutation (D79N) in the alpha2a adrenergic receptor (alpha2aAR) to investigate the role of the alpha2aAR in alpha2 agonist-evoked analgesia and adrenergic-opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective alpha2AR agonist, had no analgesic effect in D79N mice, whereas the analgesic potency of morphine (intrathecal) in this assay was not affected by the mutation. The mutation also decreased alpha2-agonist-mediated spinal analgesia and blocked the synergy seen in wild-type mice with both the delta-opioid agonist deltorphin II and the micro-opioid agonist [D-ALA2,N-Me-Phe4, Gly-ol5]-Enkephalin (DAMGO) in the substance P behavioral test. In addition, the potency of spinally administered morphine was decreased in this test, suggesting that activation of descending noradrenergic systems impinging on the alpha2aAR contributes to morphine-induced spinal inhibition in this model. These results demonstrate that the alpha2aAR subtype is the primary mediator of alpha2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids. Thus, combination therapies targeting the alpha2aAR and opioid receptors may prove useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements.