Ultrashort-loop positive feedback of corticotropin (ACTH)-releasing factor to enhance ACTH release in stress.

Abstract

Previous experiments have shown that intraventricular injection of ovine corticotropin (ACTH)-releasing factor (oCRF) in doses too low to elevate plasma ACTH by direct action on the pituitary does not lower plasma ACTH, suggesting that the peptide lacks a negative ultrashortloop feedback action to suppress its own release under resting conditions. The present study was performed to determine whether oCRF has any action to alter CRF release in stress.The peptide was injected into the third ventricle or external jugular vein of freely moving ovariectomized female rats 5 min prior to application of ether stress. When oCRF was injected into the third ventricle in doses of 500 pg (0.1 pmol) or less, there was no significant alteration in plasma ACTH prior to ether stress; however, there was a significantly enhanced increase in plasma ACTH 2 and 5 min after ether stress applied 5 min after intraventricular injection of oCRF at doses of 50 (0.01 pmol) or 150 pg (0.03 pmol). These results suggest that the peptide acts on structures adjacent to the third ventricle to augment stress-induced CRF release. To rule out the possibility that the sensitivity of the pituitary itself to CRF increases dramatically following stress, 10 or 100 ng of oCRF was injected i.v. These doses produced a significant dose-related increase in plasma ACTH at 2, 5, or 15 min. In other groups receiving the same doses of oCRF and ether stressed 5 mI later, plasma ACTH was significantly higher 2 or 5 min after ether stress when compared with plasma ACTH in etherstressed saline-injected animals. However, in contrast with the results of intraventricular injection of oCRF, the release of ACTH was no greater than that obtained by summing the independent effects of exogenous oCRF and the CRF released by stress. We conclude that CRF may have a positive ultrashortloop feedback action to enhance stress-induced ACTH release and that this enhancement is not due to increased sensitivity of anterior pituitary corticotrophs to CRF.Ultrashort-loop feedback of releasing hormones to alter their own release was postulated a number of years ago by Martini and co-workers (1). There now appears to be a number of examples of this type of interaction of peptides within the brain to alter their own release. The existence ofan ultrashortloop feedback mechanism by which somatostatin alters its own release has been suggested (2). Similarly, intraventricular injection of oxytocin appears to inhibit its own release (3).Consequently, we have looked for possible interactions of corticotropin (ACTH)-releasing factor (CRF) with other peptides in the hypothalamus. We found to our surprise that injection of ovine CRF (oCRF) into the third ventricle decreases plasma growth hormone with a minimal effective dose of 0.1 nmol. A higher dose (1.0 nmol) also decreased plasma luteinizing hormone (LH) (4, 5). In both instances, similar results have been obtained following lateral ventricular injection of the peptide (6, 7). Thus, it appears that the CRF neurons interact with those con...

Effects of intravenous and intraventricular injection of antisera directed against corticotropin-releasing factor on the secretion of anterior pituitary hormones.

“…This effect may be due to a blockade of the recently shown ultrashort loop positive feedback of CRF to enhance its own release during stress (16). It is clear that antisera injected into the ventricle can be taken up via the adjacent hypothalamic tissue and act there (17).…”

Modeling the hypothalamus–pituitary–adrenal system: homeostasis by interacting positive and negative feedback

“…We pool the integrated influences of glutamate, CRH, and ACTH from different brain regions in one molecular cue of the brain/pituitary compartment named Y (with a physiological interpretation as plasma ACTH) and suppose that the concentration y gives a positive stimulus on Z. This pooling of the CRH and ACTH compartments can be physiologically justified by the strong and fast synchrony between these hormones [20]. Additionally, Drolet et al showed that effects on CRH may be directly observed through the concentration of ACTH [21].…”

Review: Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis

“…These apparently paradoxical reports of the effects of opioids within and between species may be reconciled by proposing that, if these actions reflect short loop feedback inhibition of CRH synthesis, then the effects may be concentration-dependent, such that increasing central concentrations of POMC peptide products may stimulate CRH expression to a maximum point beyond which POMC peptides become inhibitory. The observed ability of CRH to either stimulate (Ono et al 1985) or inhibit (Calogero et al 1988b) its own release suggests a mechanism whereby -endorphin might exert opposing concentration-dependent effects upon the HPA axis, mediated by CRH.…”