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Role of Corticotropin-Releasing Factor Receptors Type 1 and 2 in Modulating the Rat Adrenocorticotropin Response to Stressors

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037; and Neurocrine Biosciences Inc., San Diego, California 92121

Address all correspondence and requests for reprints to: Catherine Rivier, Ph.D., The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: crivier{at}salk.edu.

We investigated the contribution of corticotropin-releasing factor (CRF) receptors types 1 and 2 (CRF₁ and CRF₂) in mediating the ACTH response to shock, alcohol injection, or endotoxemia in the rat. Peptidic (Astressin B and Astressin₂-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 CRF₁, penetrates the brain following systemic injection, we also compared its effect with that of Astressin B, which primarily, though not exclusively, targets CRF₁ but does not cross the blood-brain barrier. Shocks, alcohol (4.5 g/kg, intragastrically) or lipopolysaccharide (LPS, 1 µg/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 CRF₂ with Astressin₂-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 Astressin₂-B decreased ACTH levels more than NBI 30775 alone, although this difference did not reach statistical significance. Finally, blockade of CRF₁ and/or CRF₂ augmented LPS- induced TNF- and IL-6 release. Collectively, there results confirm the critical role played by CRF₁ in mediating the ACTH response to shocks, alcohol and LPS, whereas the influence of CRF₂ remains subtle. Finally, we showed that peripheral endogenous CRF restrains the ability of LPS to release cytokines.

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