Role of brain arachidonic acid cascade on central CRF1 receptor-mediated activation of sympatho-adrenomedullary outflow in rats

The present experiments were designed to characterize the mechanisms involv ed in the corticotropin releasing factor (CRF)-induced activation of centra l sympatho-adrenomedullary outflow in rats. Intracerebroventricularly (i.c. v.) administered CRF and urocortin (0.5, 1.5 and 3.0 nmol/animal) effective ly and dose-dependently elevated plasma levels of adrenaline and noradrenal ine, and the effect of urocortin was almost the same as that of CRF. The el evation of catecholamines induced by CRF and urocortin (1.5 nmol/animal) wa s reduced by CP-154,526(butyl-ethyl-(2,5-dimethyl-7-([2.3-d] pyrimidin-4-yl ]amine), a selective CRF1 receptor antagonist, in a dose dependent manner(1 .2 and/or 2.4 mu mol/animal, i.c.v.). and abolished by indomethacin(1.2 mu mol/animal, i.c.v.), an inhibitor of cyclooxygenase. Furegrelate (1.8 mu mo l/animal, i.c.v.), an inhibitor of thromboxane A, synthase, abolished the C RF-induced elevation of adrenaline, but had no effect on the evoked release of noradrenaline. These results suggest that activation of brain CRF1 rece ptor facilitates the central sympathetic and adrenomedullary outflow in dis tinct central pathways in rats: brain thromboxane A(2) is involved in the c entral adrenomedullary outflow; an active metabolite of arachidonic acid ot her than thromboxane A(2) (probably prostaglandin E-2) may be involved in t he central sympathetic outflow. (C) 2001 Elsevier Science B.V. All rights r eserved.