Department of Basic Veterinary Science, Laboratory of Physiology, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
Department of Basic Veterinary Science, Laboratory of Anatomy, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.
J Physiol. 2021 Mar;599(5):1421-1437. doi: 10.1113/JP279942. Epub 2020 Dec 28.
This 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.
We 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 measured in vivo in 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 GABA receptor 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.
本研究表明，在大鼠的结直肠中，有害刺激引起的结肠运动反应存在显著的性别差异：在雄性大鼠中，腔内给予有害刺激剂辣椒素会增强结肠运动，但在雌性大鼠中则不会。这种对有害刺激后下行神经元的差异可能是导致这种性别差异的原因。在雄性大鼠中，血清素能和多巴胺能神经元占主导地位，两者都能激活脊髓排便中枢。在雌性大鼠中，除了血清素能神经元外，GABA 能神经元也被激活。GABA 可能会与脊髓排便中枢中的 5-HT 竞争促进作用，因此，腔内给予辣椒素不会增强结肠运动。这些发现为功能性排便障碍（如肠易激综合征）中性别差异的病理生理机制提供了新的见解。
我们之前的研究表明，在雄性大鼠中，结直肠内的有害刺激通过激活下行疼痛抑制通路来增强结肠运动。由于下行疼痛抑制通路存在显著的性别差异，可以预期雄性和雌性大鼠的结肠运动调节机制不同。因此，我们旨在阐明大鼠结直肠运动对有害刺激的反应存在性别差异。在麻醉大鼠中进行体内结肠运动测量。腔内给予有害刺激剂辣椒素可增强雄性大鼠的结肠运动，但不能增强雌性大鼠的结肠运动。定量 PCR 和免疫组织化学显示，雄性和雌性大鼠背根神经节和结直肠黏膜中的 TRPV1 表达水平相当。当 GABA 受体抑制剂鞘内给予脊髓 L6-S1 水平时，即使在雌性大鼠中，腔内给予辣椒素也能促进结肠运动。在存在 GABA 阻断剂的情况下，辣椒素诱导的反应在雌性大鼠中被 5-HT2 和 -3 受体拮抗剂抑制，但不被 D2 样多巴胺受体拮抗剂抑制。我们的研究结果表明，腔内有害刺激激活了雌性大鼠中的 GABA 能和血清素能下行神经元，而在雄性大鼠中，血清素能和多巴胺能神经元占主导地位。因此，有害刺激后下行神经元的差异是导致结肠运动性别差异的原因。我们的研究结果为功能性排便障碍（如肠易激综合征）中性别差异的病理生理机制提供了新的见解。
