Fairbanks Carolyn A, Stone Laura S, Kitto Kelley F, Nguyen H Oanh, Posthumus Ivan J, Wilcox George L
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharmacol Exp Ther. 2002 Jan;300(1):282-90. doi: 10.1124/jpet.300.1.282.
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 alpha(2C)KO mice, indicating that alpha(2)AR 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 alpha(2C)AR subtype contributes to spinal antinociception and synergy with opioids.
α₂A - 肾上腺素能受体（AR）亚型介导了由α₂AR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 - Ala²，N - Me - Phe⁴，Gly⁵ - ol] - 脑啡肽和强啡肽II的抗伤害感受协同作用。α₂ - 肾上腺素能（α₂A - 、α₂B - 、α₂C - ）和阿片类（μ - 、δ - 、κ - ）亚型的不同定位表明亚型对在阿片 - 肾上腺素能镇痛协同作用中的参与情况不同。本研究应用一种新型的咪唑啉₁/α₂ - 肾上腺素能受体镇痛药莫索尼定，来测试α₂B - 和α₂C ARs在抗伤害感受和抗伤害感受协同作用中的参与情况，因为莫索尼定的脊髓抗伤害感受活性对α₂A AR的依赖性最小。鞘内注射莫索尼定在α₂A AR功能敲除（D79N - α₂A AR）的突变小鼠和α₂C AR敲除（KO）小鼠中均产生了相似的（2 - 3倍）降低。莫索尼定在α₂B KO小鼠中的效力未改变，表明该亚型不参与莫索尼定诱导的脊髓抗伤害感受。在D79N - α₂A小鼠和α₂C KO小鼠中，选择性α₂ - 受体拮抗剂SK&F 86466均剂量依赖性地抑制了莫索尼定介导的抗伤害感受，表明在缺乏α₂A - 或α₂C AR时，α₂AR激活是必需的。鞘内注射针对α₂C AR的反义寡脱氧核苷酸降低了α₂C AR免疫反应性以及莫索尼定的抗伤害感受效力。等效应线分析表明，莫索尼定 - 强啡肽抗伤害感受协同作用在D79N - α₂A小鼠中存在，但在α₂C AR - KO小鼠中不存在。这些结果证实α₂C AR亚型对脊髓抗伤害感受以及与阿片类药物的协同作用有贡献。
