Muriel Larauche1,2, Nabila Moussaoui1,2, Mandy Biraud1,2, Won Ki Bae1,2, Henri Duboc1,2, Mulugeta Million1,2, Yvette Taché1,2. 1. 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. 2. VA Greater Los Angeles Healthcare System, Los Angeles, California.
Abstract
BACKGROUND: 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). METHODS: 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 CRF1 /CRF2 (astressin-B, 30 μg/rat), CRF2 (astressin2 -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). KEY RESULTS: 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 astressin2 -B only blocked WAS-induced SIVA. CONCLUSIONS & INFERENCES: These data support a role for brain CRF signaling via CRF2 in SIVA in a model of WAS and CRD likely mediated by the activation of brain oxytocin pathway.
BACKGROUND: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). METHODS: 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 ICVsaline 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 CRF1 /CRF2 (astressin-B, 30 μg/rat), CRF2 (astressin2 -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). KEY RESULTS: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 astressin2 -B only blocked WAS-induced SIVA. CONCLUSIONS & INFERENCES: These data support a role for brain CRF signaling via CRF2 in SIVA in a model of WAS and CRD likely mediated by the activation of brain oxytocin pathway.
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