Department of Medicine, G Oppenheimer Center for Neurobiology of Stress and Resilience and CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California.
VA Greater Los Angeles Healthcare System, Los Angeles, California.
Neurogastroenterol Motil. 2019 Feb;31(2):e13489. doi: 10.1111/nmo.13489. Epub 2018 Oct 9.
Water avoidance stress (WAS) induces a naloxone-independent visceral analgesia in male rats under non-invasive conditions of monitoring. The objective of the study was to examine the role of brain CRF signaling in acute stress-induced visceral analgesia (SIVA).
Adult male Sprague-Dawley rats were chronically implanted with an intracerebroventricular (ICV) cannula. The visceromotor response (VMR) to graded phasic colorectal distension (CRD: 10, 20, 40, 60 mm Hg, 20 seconds, 4 minutes intervals) was monitored using manometry. The VMR to a first CRD (baseline) was recorded 5 minutes after an ICV saline injection, followed 1 hour later by ICV injection of either CRF (30, 100, or 300 ng and 1, 3, or 5 μg/rat) or saline and a second CRD, 5 minutes later. Receptor antagonists against CRF /CRF (astressin-B, 30 μg/rat), CRF (astressin -B, 10 μg/rat), oxytocin (tocinoic acid, 20 μg/rat), or vehicle were injected ICV 5 minutes before CRF (300 ng/rat, ICV) or 15 minutes before WAS (1 hour).
ICV CRF (100 and 300 ng) reduced the VMR to CRD at 60 mm Hg by -36.6% ± 6.8% and -48.7% ± 11.7%, respectively, vs baseline (P < 0.001), while other doses had no effect and IP CRF (10 µg/kg) induced visceral hyperalgesia. Astressin-B and tocinoic acid injected ICV induced hyperalgesia and prevented the analgesic effect of ICV CRF (300 ng/rat) and WAS, while astressin -B only blocked WAS-induced SIVA.
CONCLUSIONS & INFERENCES: These data support a role for brain CRF signaling via CRF in SIVA in a model of WAS and CRD likely mediated by the activation of brain oxytocin pathway.
在非侵入性监测条件下，水回避应激（WAS）会诱导雄性大鼠对纳洛酮不敏感的内脏镇痛。本研究的目的是探讨脑 CRF 信号在急性应激诱导的内脏镇痛（SIVA）中的作用。
成年雄性 Sprague-Dawley 大鼠被慢性植入脑室内（ICV）套管。使用测压法监测分级相性结直肠扩张（CRD：10、20、40、60mmHg，20 秒，4 分钟间隔）的内脏运动反应（VMR）。在 ICV 生理盐水注射后 5 分钟记录第一次 CRD（基线）的 VMR，1 小时后，ICV 注射 CRF（30、100 或 300ng 和 1、3 或 5μg/大鼠）或生理盐水，5 分钟后进行第二次 CRD。CRF/CRF（astressin-B，30μg/大鼠）、CRF（astressin-B，10μg/大鼠）、催产素（tocinoic acid，20μg/大鼠）或载体的受体拮抗剂在 CRF（300ng/大鼠，ICV）注射前 5 分钟或 WAS（1 小时）前 15 分钟 ICV 注射。
ICV CRF（100 和 300ng）分别使 60mmHg CRD 时的 VMR 降低了-36.6%±6.8%和-48.7%±11.7%，与基线相比（P<0.001），而其他剂量无作用，IP CRF（10μg/kg）诱导内脏痛觉过敏。ICV 注射的 astressin-B 和 tocinoic acid 诱导痛觉过敏，并阻止了 ICV CRF（300ng/大鼠）和 WAS 的镇痛作用，而 astressin-B 仅阻断了 WAS 诱导的 SIVA。
这些数据支持脑 CRF 信号通过 CRF 在 WAS 和 CRD 模型中的 SIVA 中的作用，这可能是通过脑催产素途径的激活介导的。
