Role of corticotropin-releasing factor receptors type 1 and 2 in modulating the rat adrenocorticotropin response to stressors.
We investigated the contribution of corticotropin-releasing factor (CRF) receptors types 1 and 2 (CRF(1) and CRF(2)) in mediating the ACTH response to shock, alcohol injection, or endotoxemia in the rat. Peptidic (Astressin B and Astressin(2)-B) and nonpeptidic (NBI 30775) CRF antagonists were injected iv before the stressors at doses previously shown to be effective in blocking the corresponding receptors. Because NBI 30775, which specifically blocks CRF(1), penetrates the brain following systemic injection, we also compared its effect with that of Astressin B, which primarily, though not exclusively, targets CRF(1) but does not cross the blood-brain barrier. Shocks, alcohol (4.5 g/kg, intragastrically) or lipopolysaccharide (LPS, 1 micro g/kg, iv) all significantly released ACTH. Astressin B or NBI 30775 markedly decreased the effect of shocks or alcohol and also interfered, though less significantly so, with the influence of LPS. In contrast, specific blockade of CRF(2) with Astressin(2)-B, although not significantly altering the overall ACTH response to shocks, alcohol, or LPS, slightly enhanced ACTH levels during the early phase of some of these responses. Interestingly, combined administration of NBI 30775 and Astressin(2)-B decreased ACTH levels more than NBI 30775 alone, although this difference did not reach statistical significance. Finally, blockade of CRF(1) and/or CRF(2) augmented LPS- induced TNF-alpha and IL-6 release. Collectively, there results confirm the critical role played by CRF(1) in mediating the ACTH response to shocks, alcohol and LPS, whereas the influence of CRF(2) remains subtle. Finally, we showed that peripheral endogenous CRF restrains the ability of LPS to release cytokines.
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA. crivier@salk.edu
Catherine L
CL
Rivier
Dimitri E
DE
Grigoriadis
Jean E
JE
Rivier
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004597:Electroshock; D019446:Endotoxemia; D000431:Ethanol / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013312:Stress, Physiological / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099052:CRF Receptor, Type 1
C101531:CRF receptor type 2; D002492:Central Nervous System Depressants; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D014409:Tumor Necrosis Factor-alpha; C120841:astressin B; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone