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OtherGASTROINTESTINAL PHARMACOLOGY

Central Injection of a New Corticotropin-Releasing Factor (CRF) Antagonist, Astressin, Blocks CRF- and Stress-Related Alterations of Gastric and Colonic Motor Function

Vicente Martínez, Jean Rivier, Lixin Wang and Yvette Taché
Journal of Pharmacology and Experimental Therapeutics February 1997, 280 (2) 754-760;
Vicente Martínez
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Jean Rivier
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Lixin Wang
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Yvette Taché
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Abstract

The influence of central injection of a new corticotropin releasing factor (CRF) antagonist, astressin, {cyclo(30–33)[D-Phe12,Nle21,38,Glu30,Lys33]r/hCRF12–41)}, on exogenous and endogenous CRF-induced gastric ileus and stimulation of bowel discharges was investigated in conscious rats. Intracisternal (ic) CRF (0.6 μg) reduced gastric emptying of a noncaloric solution to 17.1 ± 4.9% compared with 50.1 ± 4.6% in control group injected ic with vehicle. Astressin (1, 3 and 10 μg, ic) dose dependently prevented ic CRF-induced delayed gastric emptying by 33, 100 and 100%, respectively, and had no effect on basal gastric emptying. Abdominal surgery with cecal manipulation (1 min) reduced gastric emptying to 19.8 ± 5.5% 3 hr postsurgery compared with 59.9 ± 5.2% after anesthesia alone plus ic vehicle. Astressin (1, 3 and 10 μg, ic) prevented postoperative gastric ileus by 56, 93 and 92%, respectively. Intracerebroventricular CRF (0.6 μg) and water-avoidance stress stimulated pellet output (number/60 min) to 5 ± 1 and 11 ± 2, respectively, compared with no fecal pellet output after icv vehicle and no exposure to stress. Astressin (3 and 10 μg, icv) blocked exogenous CRF action by 47 and 63%, respectively, and colonic response to stress by 0 and 54%, respectively. These data indicate that astressin injected into the CSF at low doses (1–10 μg) has an antagonistic action against CRF and stress-related alterations of gastrointestinal motor function, without an intrinsic effect in these in vivo systems. Astressin may be a useful tool to explore functional CRF-dependent physiological pathways in specific brain nuclei.

Footnotes

  • Send reprint requests to: Dr. Vicente Martínez, Bld 115, Room 203, West Los Angeles VA Medical Center, 11301 Wilshire Blvd., Los Angeles, CA 90073.

  • ↵1 This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, Grants DK-33061 (Y.T.), DK-41301 (Center Grant, Animal Core, Y.T.) and DK-26741 (J.R.) and the National Institute of Mental Health Grant MH-00663 (Y.T.).

  • ↵2 Current address: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA.

  • Abbreviations:
    ACTH
    adrenocorticotropin hormone
    ANOVA
    analysis of variance
    CSF
    cerebrospinal fluid
    CRF
    corticotropin-releasing factor
    r/hCRF
    rat/human corticotropin-releasing factor
    ic
    intracisternal
    icv
    intracerebroventricular
    α-helical CRF9–41
    [Met18,Lys23,Glu27,29,40,Ala32,41,Leu33,36,38]h/rCRF9–41
    D-Phe CRF12–41
    [D-Phe12,Nle21,38,CαMeLeu37]CRF12–41
    GI
    gastrointestinal
    PVN
    paraventricular nucleus of the hypothalamus
    • Received June 17, 1996.
    • Accepted October 30, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 2
1 Feb 1997
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OtherGASTROINTESTINAL PHARMACOLOGY

Central Injection of a New Corticotropin-Releasing Factor (CRF) Antagonist, Astressin, Blocks CRF- and Stress-Related Alterations of Gastric and Colonic Motor Function

Vicente Martínez, Jean Rivier, Lixin Wang and Yvette Taché
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 754-760;

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OtherGASTROINTESTINAL PHARMACOLOGY

Central Injection of a New Corticotropin-Releasing Factor (CRF) Antagonist, Astressin, Blocks CRF- and Stress-Related Alterations of Gastric and Colonic Motor Function

Vicente Martínez, Jean Rivier, Lixin Wang and Yvette Taché
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 754-760;
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