State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20115-9. doi: 10.1073/pnas.1009923107. Epub 2010 Nov 1.
Sexually dimorphic nociception and opioid antinociception is very pervasive but poorly understood. We had demonstrated that spinal morphine antinociception in females, but not males, requires the concomitant activation of spinal μ- and κ-opioid receptors (MOR and KOR, respectively). This finding suggests an interrelationship between MOR and KOR in females that is not manifest in males. Here, we show that expression of a MOR/KOR heterodimer is vastly more prevalent in the spinal cord of proestrous vs. diestrous females and vs. males. Cross-linking experiments in combination with in vivo pharmacological analyses indicate that heterodimeric MOR/KOR utilizes spinal dynorphin 1-17 as a substrate and is likely to be the molecular transducer for the female-specific KOR component of spinal morphine antinociception. The activation of KOR within the heterodimeric MOR/KOR provides a mechanism for recruiting spinal KOR-mediated antinociception without activating the concomitant pronociceptive functions that monomeric KOR also subserves. Spinal cord MOR/KOR heterodimers represent a unique pharmacological target for female-specific pain control.
性二态性疼痛和阿片类药物镇痛非常普遍，但知之甚少。我们已经证明，雌性而不是雄性的脊髓吗啡镇痛需要同时激活脊髓 μ 和 κ 阿片受体（分别为 MOR 和 KOR）。这一发现表明，雌性体内 MOR 和 KOR 之间存在相互关系，而雄性则没有。在这里，我们表明，与发情期和发情期相比，发情前期雌性和雄性脊髓中 MOR/KOR 异二聚体的表达更为普遍。交联实验结合体内药理学分析表明，异二聚体 MOR/KOR 利用脊髓强啡肽 1-17 作为底物，并且可能是脊髓吗啡镇痛中雌性特异性 KOR 成分的分子转导器。异二聚体 MOR/KOR 内 KOR 的激活为招募脊髓 KOR 介导的镇痛提供了一种机制，而不会激活单体 KOR 也具有的伴随促痛作用。脊髓 MOR/KOR 异二聚体代表了一种用于女性特异性疼痛控制的独特药理学靶标。
