Kumar Arjun, Storman Emiliya M, Liu Nai-Jiang, Gintzler Alan R
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, N.Y., USA.
Neuroendocrinology. 2015;102(1-2):33-43. doi: 10.1159/000430817. Epub 2015 Apr 29.
BACKGROUND/AIMS: Male and female rats differ in their ability to utilize spinal endomorphin 2 (EM2; the predominant mu-opioid receptor ligand in spinal cord) and in the mechanisms that underlie spinal EM2 analgesic responsiveness. We investigated the relevance of spinal estrogen receptors (ERs) to the in vivo regulation of spinal EM2 release.
ER antagonists were administered directly to the lumbosacral spinal cord of male and female rats, intrathecal perfusate was collected, and resulting changes in EM2 release were quantified using a plate-based radioimmunoassay.
Intrathecal application of an antagonist of either estrogen receptor-α (ERα) or the ER GPR30 failed to alter spinal EM2 release. Strikingly, however, the concomitant blockade of ERα and GPR30 enhanced spinal EM2 release. This effect was sexually dimorphic, being absent in males. Furthermore, the magnitude of the enhancement of spinal EM2 release in females was dependent upon estrous cycle stage, suggesting a relationship with circulating levels of 17β-estradiol. The rapid onset of enhanced EM2 release following intrathecal application of ERα/GPR30 antagonists (within 30-40 min) suggests mediation via ERs in the plasma membrane, not the nucleus. Notably, both ovarian and spinally synthesized estrogens are essential for membrane ER regulation of spinal EM2 release.
These findings underscore the importance of estrogens for the regulation of spinal EM2 activity and, by extension, endogenous spinal EM2 antinociception in females. Components of the spinal estrogenic mechanism(s) that suppress EM2 release could represent novel drug targets for improving utilization of endogenous spinal EM2, and thereby pain management in women.
背景/目的：雄性和雌性大鼠在利用脊髓内的内吗啡肽2（EM2；脊髓中主要的μ阿片受体配体）的能力以及脊髓EM2镇痛反应的潜在机制方面存在差异。我们研究了脊髓雌激素受体（ERs）与脊髓EM2释放的体内调节之间的相关性。
将ER拮抗剂直接注射到雄性和雌性大鼠的腰骶脊髓，收集鞘内灌注液，并使用基于板的放射免疫测定法定量由此引起的EM2释放变化。
鞘内应用雌激素受体-α（ERα）拮抗剂或ER GPR30均未改变脊髓EM2释放。然而，令人惊讶的是，同时阻断ERα和GPR30可增强脊髓EM2释放。这种效应具有性别差异，在雄性中不存在。此外，雌性脊髓EM2释放增强的幅度取决于发情周期阶段，表明与17β-雌二醇的循环水平有关。鞘内应用ERα/GPR30拮抗剂后EM2释放增强的快速起效（在30-40分钟内）表明是通过质膜而非细胞核中的ER介导的。值得注意的是，卵巢和脊髓合成的雌激素对于脊髓EM2释放的膜ER调节都是必不可少的。
这些发现强调了雌激素对脊髓EM2活性调节的重要性，并进而对雌性内源性脊髓EM2镇痛作用的重要性。抑制EM2释放的脊髓雌激素机制的组成部分可能代表了改善内源性脊髓EM2利用从而改善女性疼痛管理的新型药物靶点。
