α2C-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy
α2C-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy
复制标题
DOI：
10.1124/jpet.300.1.282
复制
发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Wilcox, GL
中科院分区：
文献类型：
--
作者：
Fairbanks, CA;Stone, LS;Wilcox, GL
α（2A）-肾上腺素能受体（AR）亚型介导由α（2）AR激动剂可乐定、右美托咪定、去甲肾上腺素和5-溴-N-（4，5-二氢-1H-咪唑-2-基）-6-喹喔啉胺（UK-14，304）诱导的抗伤害感受，以及UK-14，304与阿片类激动剂[D-Ala（2）、N-Me-Phe（4）、Gly（5）-ol]-脑啡肽和deltorphin II的抗伤害感受协同作用。α（2）-肾上腺素能（α（2A）-、α（2B）-、α（2C）-）和阿片样物质（μ-、δ-、κ-）亚型的差异定位表明阿片样物质-肾上腺素能镇痛协同作用中亚型对的差异参与。本研究应用一种新型咪唑啉（1）/α（2）-肾上腺素能受体镇痛药莫索尼定，检测α（2B）-和α（2C）AR参与抗伤害感受和抗伤害感受协同作用，因为莫索尼定的脊髓抗伤害感受活性显示对α（2A）AR的依赖性最小。鞘内注射莫索尼定在α（2A）AR功能性敲除突变小鼠（D 79 N-alpha（2A）AR）和α（2C）AR敲除（KO）小鼠中产生相似（2-3倍）降低。莫索尼定的效力在α（2B）KO小鼠中未发生改变，表明该亚型不参与莫索尼定诱导的脊髓抗伤害感受。在D 79 N-α（2A）小鼠和α（2C）KO小鼠中，莫索尼定介导的抗伤害感受被选择性α（2）受体拮抗剂SK&F 86466剂量依赖性地抑制，表明α（2A）或α（2C）AR缺失时需要α 2AR激活。脊髓给药针对α（2C）AR的反义寡脱氧核苷酸降低α（2C）AR免疫反应性和莫索尼定的抗伤害感受效力。等效辐射图分析表明，莫索尼定-Deltorphin抗伤害感受协同作用存在于D 79 N-alpha（2A）小鼠中，但不存在于alpha（2C）AR-KO小鼠中。这些结果证实，α，β AR亚型有助于脊髓抗伤害感受和与阿片类药物的协同作用。
The alpha(2A)-adrenergic receptor (AR) subtype mediates antinociception induced by the alpha(2)AR agonists clonidine, dexmedetomidine, norepinephrine, and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304) as well as antinociceptive synergy of UK-14,304 with opioid agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and deltorphin II. Differential localization of alpha(2)-adrenergic (alpha(2A)-, alpha(2B)-, alpha(2C)-) and opioid (mu-, delta-, kappa-) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline(1)/alpha(2)-adrenergic receptor analgesic, moxonidine, to test for involvement of alpha(2B)- and alpha(2C)ARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on alpha(2A)AR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of alpha(2A)AR (D79N-alpha(2A)AR) and alpha(2C)AR knockout (KO) mice. The potency of moxonidine was not altered in alpha(2B)KO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective alpha(2)-receptor antagonist SK&F 86466 in both D79N-alpha(2A) mice and a,,KO mice, indicating that a2AR activation is required in the absence of either alpha(2A)- or alpha(2C)AR. Spinal administration of antisense oligodeoxynucleotides directed against the alpha(2C)AR decreased both alpha(2C)AR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-alpha(2A) mice but not in the alpha(2C)AR-KO mice. These results confirm that the a,,AR subtype contributes to spinal antinociception and synergy with opioids.