Corticotropin-releasing hormone receptor 1 antagonist blocks brain-gut activation induced by colonic distention in rats.
OBJECTIVE
The corticotropin-releasing hormone receptor 1 mediates stress-induced changes in colonic motor activity and emotion. We tested the hypothesis that pretreatment with JTC-017, a specific corticotropin-releasing hormone receptor 1 antagonist, blocks colorectal distention-induced hippocampal noradrenaline release and visceral perception in rats. We also investigated whether pretreatment with JTC-017 blocks acute or chronic colorectal distention-induced adrenocorticotropic hormone release, anxiety, and stress-induced changes in colonic motility.


METHODS
Rats were pretreated intrahippocampally with alpha-helical corticotropin-releasing hormone (1.25 microg/kg; vehicle), a nonspecific corticotropin-releasing hormone receptor antagonist, or intraperitoneally with JTC-017 (10 mg/kg). Hippocampal noradrenaline release after microdialysis and the frequency of abdominal contractions were measured in response to acute colorectal distention. Plasma adrenocorticotropic hormone levels, anxiety-related behavior, and stress-induced changes in colonic motility were evaluated after acute or chronic colorectal distention followed by exposure to an elevated plus maze.


RESULTS
Administration of alpha-helical corticotropin-releasing hormone or JTC-017 significantly attenuated hippocampal noradrenaline release and reduced the frequency of abdominal contractions induced by acute distention. In addition, JTC-017 significantly reduced plasma adrenocorticotropic hormone and anxiety after acute distention. After chronic distention, changes in plasma adrenocorticotropic hormone and anxiety were not significant because of habituation. In contrast, a significant increase in fecal pellet output during the elevated plus maze was observed after chronic distention. This increase in fecal pellet output was blocked by pretreatment with JTC-017.


CONCLUSIONS
Our results suggest that JTC-017, a specific corticotropin-releasing hormone receptor 1 antagonist, attenuates hippocampal noradrenaline release, visceral perception, adrenocorticotropic hormone release, and anxiety after acute colorectal distention in rats. In addition, JTC-017 blocks stress-induced changes in colonic motility after chronic colorectal distention in rats.
Saito
Kumi
K
Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Kasai
Toshiyuki
T
Nagura
Yohko
Y
Ito
Hitomi
H
Kanazawa
Motoyori
M
Fukudo
Shin
S
D000009:Abdominal Muscles / Q000502:physiology; D000208:Acute Disease; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001522:Behavior, Animal; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002404:Catheterization; D002908:Chronic Disease; D003106:Colon / Q000294:innervation / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
D001549:Benzamides; D006727:Hormone Antagonists; C506580:JTC-017; D018019:Receptors, Corticotropin-Releasing Hormone; C069206:alpha helical corticotropin-releasing hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D009638:Norepinephrine