The adrenocorticotropin response to interleukin-1 beta instilled into the rat median eminence depends on the local release of catecholamines.
Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRF but is unable to cross the blood brain barrier. Recently, it was reported that IL-1 beta, instilled directly into the hypothalamic median eminence (ME), rapidly induced ACTH secretion. Thus, due to the lack of a blood brain barrier the ME appears to be a site whereby iv IL-1 beta can access the brain to stimulate CRF and, consequently, ACTH secretion. To evaluate the role of central catecholamines in this process, 250 g male rats were lesioned with 6-hydroxy-dopamine instilled into the lateral ventricle. Ten days later, rats received recombinant h-IL-1 beta (10 or 30 ng) into the ME and blood was sampled via indwelling jugular cannulae. The ACTH response to IL-1 beta, 30 ng, was reduced by approximately 50% in the lesioned rats (P = 0.05), and it was abolished in those receiving IL-1 beta, 10 ng (P less than 0.05). Moreover, in rats given iv IL-1 beta (1 microgram), 6-hydroxy-dopamine significantly reduced the ACTH response by more than 50% (P less than 0.001). To determine the effect of acute epinephrine depletion, 2,3 dichloro-alpha-methylbenzylamine (DCMB, 60 mg/kg BW) and SKF64139 (SKF) (100 mg/kg BW), inhibitors of the enzyme which converts norepinephrine to epinephrine, were administered ip 4 h before intra-ME IL-1 beta (30 ng). DCMB reduced the ACTH response by 80% and SKF reduced it to its own baseline. LY 10853, which acutely depletes both norepinephrine and epinephrine, also reduced the ACTH response by 80%. Because of the reported capacities of DCMB and SKF to block alpha 2 adrenoreceptors in vitro, yohimbine, an alpha 2 receptor antagonist, was studied. Intra-ME yohimbine failed to inhibit the ACTH response to intra-ME IL-1 beta. In contrast, a significant (P less than 0.01) dose-dependent reduction in the ACTH response to intra-ME IL-1 beta (30 ng) was observed in rats pretreated with either a nonselective alpha or beta adrenoreceptor antagonist (phentolamine, 2-40 micrograms or propranolol, 2-20 micrograms, respectively, into the ME). In contrast, intra-ME phentolamine, 20 micrograms, failed to reduce the ACTH response to iv CRF, 1 microgram/kg BW. Thus, the secretion of ACTH stimulated by the action of IL-1 beta at the ME depends, in part, on the local secretion of norepinephrine and epinephrine interacting with both alpha and beta adrenergic receptors.
Matta
S
S
Endocrine-Neuroscience Research Laboratories, Hennepin County Medical Center, Minneapolis, Minnesota.
Singh
J
J
Newton
R
R
Sharp
B M
BM
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D006892:Hydroxydopamines / Q000494:pharmacology; D007033:Hypothalamus, Middle / Q000378:metabolism; D007267:Injections; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008473:Median Eminence / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D013565:Sympatholytics / Q000494:pharmacology
D002395:Catecholamines; D006892:Hydroxydopamines; D007375:Interleukin-1; D009498:Neurotoxins; D013565:Sympatholytics; D016627:Oxidopamine; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone