Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats
Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats
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DOI：
10.1113/jp279942
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发表时间：
2020-12-28
影响因子：
5.5
通讯作者：
Shimizu，Yasutake
中科院分区：
文献类型：
--
作者：
Horii，Kazuhiro;Ehara，Yuka;Shimizu，Yasutake
关键点本研究表明，大鼠结肠直肠运动对伤害性刺激的反应存在显著的性别差异：结肠内注射辣椒素可增强雄性大鼠的结肠运动，但雌性大鼠则无此作用。伤害性刺激后从大脑到脊髓的下行神经元的差异可能是造成性别差异的原因。在雄性大鼠中，多巴胺能神经元和多巴胺能神经元主要被激活，两者都激活脊髓排便中枢。在雌性大鼠中，除了多巴胺能神经元外，GABA能神经元也被激活。GABA可能在脊髓排便中心竞争5-HT的易化作用，因此，结肠内给予辣椒素并不能增强结肠的运动性。这些发现为功能性排便障碍如肠易激综合征的性别差异的病理生理机制提供了新的见解。在雄性大鼠中的抑制途径。可以预期，由于下行疼痛抑制通路的显著性别差异，男性和女性的大肠运动的调节机制不同。因此，我们的目的是澄清性别差异的结肠直肠运动反应的伤害性刺激在大鼠。在活体麻醉大鼠上测量结直肠运动。在雄性大鼠的结肠直肠腔内给予有害的刺激物辣椒素可增强结肠直肠运动，但在雌性大鼠中则不然。定量PCR和免疫组化结果表明，TRPV1在背根神经节和结直肠粘膜中的表达水平在雄性和雌性大鼠中相当。当GABAA受体抑制剂鞘内给药到脊髓的L6-S1水平时，即使在雌性大鼠中，结肠内辣椒素也能促进结肠直肠运动。鞘内注射5-HT 2和3受体拮抗剂可抑制雌性大鼠中存在GABA阻滞剂时辣椒素诱导的反应，但D2样多巴胺受体拮抗剂则不能抑制。我们的研究结果表明，结肠内伤害性刺激激活GABA能和多巴胺能下行神经元在雌性大鼠，而多巴胺能和多巴胺能神经元主要激活在雄性大鼠。因此，伤害性刺激后下行神经元的差异可能是结直肠运动性二态反应的原因。我们的研究结果提供了一个新的见解，在功能性排便障碍，如肠易激综合征的性别差异的病理生理机制。
Key pointsThis study showed a remarkable sex difference in responses of colorectal motility to noxious stimuli in the colorectum in rats: colorectal motility was enhanced in response to intracolonic administration of a noxious stimulant, capsaicin, in male rats but not in female rats.The difference in descending neurons from the brain to spinal cord operating after noxious stimulation could be responsible for the sex difference.In male rats, serotoninergic and dopaminergic neurons are dominantly activated, both of which activate the spinal defaecation centre.In female rats, GABAergic neurons in addition to serotoninergic neurons are activated. GABA may compete for facilitative action of 5‐HT in the spinal defaecation centre, and thereby colorectal motility is not enhanced in response to intracolonic administration of capsaicin.The findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.AbstractWe previously demonstrated that noxious stimuli in the colorectum enhance colorectal motility through activation of descending pain inhibitory pathways in male rats. It can be expected that the regulatory mechanisms of colorectal motility differ in males and females owing to remarkable sex differences in descending pain inhibitory pathways. Thus, we aimed to clarify sex differences in responses of colorectal motility to noxious stimuli in rats. Colorectal motility was measuredin vivoin anaesthetized rats. Administration of a noxious stimulant, capsaicin, into the colorectal lumen enhanced colorectal motility in male rats but not in female rats. Quantitative PCR and immunohistochemistry showed that TRPV1 expression levels in the dorsal root ganglia and in the colorectal mucosa were comparable in male and female rats. When a GABAAreceptor inhibitor was intrathecally administered to the L6–S1 level of the spinal cord, colorectal motility was facilitated in response to intracolonic capsaicin even in female rats. The capsaicin‐induced response in the presence of the GABA blocker in female rats was inhibited by intrathecal administration of 5‐HT2 and ‐3 receptor antagonists but not by a D2‐like dopamine receptor antagonist. Our findings demonstrate that intracolonic noxious stimulation activates GABAergic and serotoninergic descending neurons in female rats, whereas serotoninergic and dopaminergic neurons are dominantly activated in male rats. Thus, the difference in the descending neurons operating after noxious stimulation would be responsible for the sexually dimorphic responses of colorectal motility. Our findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.