Formation of μ-/κ-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia
Formation of μ-/κ-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia
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DOI：
10.1073/pnas.1009923107
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发表时间：
2010-11-16
影响因子：
11.1
通讯作者：
Gintzler, Alan R.
中科院分区：
文献类型：
--
作者：
Chakrabarti, Sumita;Liu, Nai-Jiang;Gintzler, Alan R.
性二态性伤害感受和阿片类抗伤害感受是非常普遍的，但知之甚少。我们已经证明，女性而非男性的脊髓吗啡镇痛作用需要同时激活脊髓μ-和κ-阿片受体（分别为莫尔和KOR）。这一发现表明，莫尔和KOR之间的相互关系，在女性是不明显的男性。在这里，我们表明，表达的莫尔/KOR异二聚体是非常普遍的，在脊髓的动情前期与动情间期的女性和男性。结合体内药理学分析的交联实验表明，异二聚体莫尔/KOR利用脊髓强啡肽1-17作为底物，并且可能是脊髓吗啡抗伤害感受的女性特异性KOR组分的分子转导物。异源二聚体莫尔/KOR中KOR的激活提供了一种募集脊髓KOR介导的抗伤害感受的机制，而不激活单体KOR也支持的伴随的原伤害感受功能。脊髓莫尔/KOR异二聚体代表了女性特异性疼痛控制的独特药理学靶点。
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 mu- and kappa-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.