Höcker Jan, Böhm Ruwen, Meybohm Patrick, Gruenewald Matthias, Renner Jochen, Ohnesorge Henning, Scholz Jens, Bein Berthold
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
J Pharm Pharmacol. 2009 Jul;61(7):901-10. doi: 10.1211/jpp/61.07.0009.
alpha(2)-Adrenergic and mu-opioid receptors belong to the rhodopsin family of G-protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with alpha(2)-adrenoceptor-subtypes in mice lacking one individual alpha(2)-adrenoceptor-subtype (alpha(2)-adrenoceptor knockout).
Opioid interaction with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]paraiodoclonidine from alpha(2)-adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified.
Morphine but not fentanyl or naloxone provoked dose-dependent displacement of [(125)I]paraiodoclonidine from all alpha(2)-adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of alpha(2A)-adrenoceptor knockout mice.
Our results indicated that morphine interacted with alpha(2)-adrenoceptors showing higher affinity for the alpha(2B) and alpha(2C) than for the alpha(2A) subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to alpha(2)-adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.
α₂肾上腺素能受体和μ阿片受体属于G蛋白偶联受体的视紫红质家族，并通过相似的信号转导途径介导镇痛作用。以往研究揭示了这两种受体系统之间存在直接的功能相互作用，包括协同和相加效应。为评估潜在机制，我们研究了吗啡和芬太尼在缺乏单个α₂肾上腺素能受体亚型（α₂肾上腺素能受体基因敲除）的小鼠中是否与α₂肾上腺素能受体亚型相互作用。
通过定量受体放射自显影术，在α₂A -、α₂B -或α₂C -肾上腺素能受体缺陷小鼠的脑片中研究阿片类药物与α₂肾上腺素能受体的相互作用。分析了不同浓度的吗啡、芬太尼和纳洛酮对不同脑区α₂肾上腺素能受体上放射性标记的α₂肾上腺素能受体激动剂[¹²⁵I]对碘氯苯胍的置换作用。定量了两种阿片类药物对不同脑区α₂肾上腺素能受体亚型的结合亲和力。
在分析的脑区中，吗啡而非芬太尼或纳洛酮引起[¹²⁵I]对碘氯苯胍从所有α₂肾上腺素能受体亚型上的剂量依赖性置换。在α₂A -肾上腺素能受体基因敲除小鼠的皮质、延髓和脑桥中，结合亲和力最高。
我们的结果表明，吗啡与α₂肾上腺素能受体相互作用，对α₂B和α₂C亚型的亲和力高于α₂A亚型。相比之下，芬太尼和纳洛酮对α₂肾上腺素能受体没有任何相关亲和力。这种效应可能会影响吗啡的药理作用。
