Sasaki Kazumasu, Sumiyoshi Akira, Nonaka Hiroi, Kasahara Yoshiyuki, Ikeda Kazutaka, Hall F Scott, Uhl George R, Watanabe Masahiko, Kawashima Ryuta, Sora Ichiro
Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Br J Pharmacol. 2015 Jan;172(2):654-67. doi: 10.1111/bph.12807. Epub 2014 Sep 5.
μ Opioid receptor knockout (MOP-KO) mice display several behavioural differences from wild-type (WT) littermates including differential responses to nociceptive stimuli. Brain structural changes have been tied to behavioural alterations noted in transgenic mice with targeting of different genes. Hence, we assess the brain structure of MOP-KO mice.
Magnetic resonance imaging (MRI) voxel-based morphometry (VBM) and histological methods were used to identify structural differences between extensively backcrossed MOP-KO mice and WT mice.
MOP-KO mice displayed robust increases in regional grey matter volume in olfactory bulb, several hypothalamic nuclei, periaqueductal grey (PAG) and several cerebellar areas, most confirmed by VBM analysis. The largest increases in grey matter volume were detected in the glomerular layer of the olfactory bulb, arcuate nucleus of hypothalamus, ventrolateral PAG (VLPAG) and cerebellar regions including paramedian and cerebellar lobules. Histological analyses confirm several of these results, with increased VLPAG cell numbers and increased thickness of the olfactory bulb granule cell layer and cerebellar molecular and granular cell layers.
MOP deletion causes previously undescribed structural changes in specific brain regions, but not in all regions with high MOP receptor densities (e.g. thalamus, nucleus accumbens) or that exhibit adult neurogenesis (e.g. hippocampus). Volume differences in hypothalamus and PAG may reflect behavioural changes including hyperalgesia. Although the precise relationship between volume change and MOP receptor deletion was not determined from this study alone, these findings suggest that levels of MOP receptor expression may influence a broader range of neural structure and function in humans than previously supposed.
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
μ阿片受体基因敲除（MOP-KO）小鼠与野生型（WT）同窝小鼠表现出多种行为差异，包括对伤害性刺激的不同反应。脑结构变化与转基因小鼠中因不同基因靶向而出现的行为改变有关。因此，我们评估了MOP-KO小鼠的脑结构。
采用基于磁共振成像（MRI）体素的形态学测量（VBM）和组织学方法，以确定经过广泛回交的MOP-KO小鼠与WT小鼠之间的结构差异。
MOP-KO小鼠在嗅球、多个下丘脑核团、导水管周围灰质（PAG）和多个小脑区域的区域灰质体积显著增加，大多数结果通过VBM分析得到证实。灰质体积增加最大的区域是嗅球的肾小球层、下丘脑弓状核、腹外侧PAG（VLPAG）以及包括旁正中小叶和小脑小叶在内的小脑区域。组织学分析证实了其中一些结果，VLPAG细胞数量增加，嗅球颗粒细胞层以及小脑分子层和颗粒细胞层厚度增加。
MOP缺失导致特定脑区出现先前未描述的结构变化，但并非所有MOP受体密度高的区域（如丘脑、伏隔核）或有成年神经发生的区域（如海马体）都有这种变化。下丘脑和PAG的体积差异可能反映了包括痛觉过敏在内的行为变化。尽管仅从本研究中无法确定体积变化与MOP受体缺失之间的确切关系，但这些发现表明，MOP受体表达水平对人类神经结构和功能的影响范围可能比之前认为的更广。
本文是关于阿片类药物：功能选择性新途径主题部分的一部分。要查看本部分的其他文章，请访问http://dx.doi.org/10.1111/bph.2015.172.issue-2。
