Okumura Toshikatsu, Nozu Tsukasa, Kumei Shima, Takakusaki Kaoru, Ohhira Masumi
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan; Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
Department of Regional Medicine and Education, Asahikawa Medical University, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
Brain Res. 2018 May 1;1686:48-54. doi: 10.1016/j.brainres.2018.02.024. Epub 2018 Feb 21.
Increasing evidence implicates brain ghrelin in a wide variety of physiological functions. Among its gastrointestinal functions, ghrelin is known to act centrally to regulate gastrointestinal motility. Visceral sensation is one of the key gastrointestinal functions controlled by the central nervous system. Little is, however, known about the role of central ghrelin in visceral sensation. The present study thus aimed to clarify whether brain ghrelin is involved in visceral sensation. Visceral sensation was evaluated by the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered ghrelin increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. By contrast, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin altered the threshold volume. Pretreatment with subcutaneous injection of either naloxone hydrochloride or sulpiride, a dopamine D2 receptor antagonist, significantly blocked ghrelin-induced visceral antinociception; furthermore, neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, SCH23390, a dopamine D1 receptor antagonist, nor DPCPX, an adenosine A1 receptor antagonist, blocked antinociception. Although intracisternal SB334867, an orexin 1 receptor antagonist, alone failed to change the threshold volume, centrally injected SB334867 potently blocked ghrelin-induced antinociceptive action during colonic distension. These results provide the first evidence that ghrelin acts centrally in the brain to enhance antinociceptive response to colonic distension through the central opioid system, dopamine D2 signaling, and the orexinergic pathway.
越来越多的证据表明，脑内胃饥饿素参与多种生理功能。在其胃肠道功能中，已知胃饥饿素可通过中枢作用调节胃肠蠕动。内脏感觉是中枢神经系统控制的关键胃肠道功能之一。然而，关于中枢胃饥饿素在内脏感觉中的作用却知之甚少。因此，本研究旨在阐明脑内胃饥饿素是否参与内脏感觉。通过在清醒大鼠中进行结肠扩张诱导的腹部回撤反射（AWR）来评估内脏感觉。脑池内注射胃饥饿素以剂量依赖的方式增加了结肠扩张诱导的AWR的阈值体积。相比之下，腹腔注射胃饥饿素或脑池内注射去酰基胃饥饿素均未改变阈值体积。皮下注射盐酸纳洛酮或多巴胺D2受体拮抗剂舒必利预处理可显著阻断胃饥饿素诱导的内脏镇痛作用；此外，皮下注射外周选择性阿片受体拮抗剂甲硫氨酸纳洛酮、多巴胺D1受体拮抗剂SCH23390或腺苷A1受体拮抗剂DPCPX均未阻断镇痛作用。虽然脑池内注射食欲素1受体拮抗剂SB334867单独未能改变阈值体积，但脑内注射SB334867可有效阻断结肠扩张期间胃饥饿素诱导的镇痛作用。这些结果首次证明，胃饥饿素通过中枢阿片系统、多巴胺D2信号通路和食欲素能途径在脑内发挥作用，增强对结肠扩张的镇痛反应。
