Effect of non-peptide corticotropin-releasing factor receptor type 1 antagonist on adrenocorticotropic hormone release and interleukin-1 receptors followed by stress

Abstract

Previous studies demonstrated that ether-laparotomy significantly increased iodine-125-labeled interleukin-1α ([ 125I]IL-1α) binding in the mouse anterior pituitary at 2 h after the onset of stress. Corticotropin-releasing factor (CRF) receptor antagonist, D-Phe CRF (12-41), abolished ether-laparotomy-induced increase in [ 125I]IL-1α binding in the pituitary, showing that CRF plays a pivotal role in the regulation of IL-1 receptors under stress conditions. In an attempt to define the effect of CRA 1000 (2-( N-(2-methylthio-4-isopropylphenyl)- N-ethylamino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine), a non-peptide CRF receptor type 1 antagonist on the regulation of hypothalamic–pituitary–adrenal (HPA) axis and IL-1 receptors in the mouse, we measured plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, [ 125I]IL-1α binding and the expression of transcripts for type 1 IL-1 receptor (IL-1R1 mRNA) in the pituitary at 2 h after endotoxin lipopolysaccharide (LPS) treatment or ether-laparotomy stress with or without CRA 1000 pretreatment. A single injection of LPS dramatically increased plasma ACTH and corticosterone levels compared with saline injection. In contrast, plasma ACTH levels were significantly attenuated in response to one LPS injection following oral CRA 1000 pretreatment. LPS-induced plasma corticosterone levels tended to be lower after CRA 1000 pretreatment but it did not reach statistical significance. Ether-laparotomy stress significantly increased plasma ACTH and corticosterone levels at 2 h after the onset of stress and CRA 1000 pretreatment did not affect the peak ACTH and corticosterone levels following stress. Ether-laparotomy stress resulted in a robust increase in [ 125I]IL-1α binding and IL-1R1 mRNA levels in the pituitary. CRA 1000 pretreatment significantly decreased ether-laparotomy stress-induced IL-1R1 mRNA levels but did not affect [ 125I]IL-1α binding. Pretreatment with CRA 1000 without stress significantly increased [ 125I]IL-1α binding and IL-1R1 mRNA levels compared with those in vehicle pretreatment. These data demonstrate differential effects of CRA 1000 in HPA axis following endotoxin and ether-laparotomy stress and complex interactions between CRF and IL-1 receptors during stress.