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Rate-Sensitive Glucocorticoid Feedback Inhibition of Adrenocorticotropin and β-Endorphin/β-Lipotropin Secretion in Rats^*

Division of Endocrinology and Metabolism, Department of Medicine, University of Kentucky and Veterans Administration Medical Center Lexington, Kentucky 40536 Departments of Medicine and Physiology, University of Toronto Toronto, Canada M5S 1AB

Address all correspondence to: Errol B. De Souza, Neuroscience Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland 21224.

Abstract

In the present study, we present physiological evidence for rate-sensitive, fast feedback inhibition of secretion of ACTH and β-endorphin (βEND)-related peptides. We used a 2 min restraint stress to physiologically increase plasma corticosterone, then examined the plasma responses of immunoreactive ACTH and βEND plus β-lipotropin (beta;END/(8LPH) to a subsequent restraint stress. After onset of this stress, plasma corticosterone increased from 2.5–10 min at a rate of 120 nM min^–1, then remained at a peak from 10–15 min. A single 2 min restraint stress produced peak plasma levels of ACTH and βEND/βLPH 2.5 min after onset of the stress, and these plasma concentrations declined after this initial stress at rates of 2.7 and 7.4 pM min^–1, respectively. Application of a second restraint stress at the time of the peak corticosterone response produced plasma ACTH and βEND/βLPH responses similar to those after the first stress. Application of a second stress during the period of significant rate-rise of corticosterone in plasma did not result in decreased incremental responses of plasma ACTH or βEND/βSLPH. However, the rates of decline of plasma ACTH and βEND/βLPH of 7.6 and 32 pM min^–1, respectively, from peak levels, were significantly greater after this second stress applied during the period of significant increase in plasma corticosterone concentration than the corresponding rates of decline observed after the initial stress or after a subsequent stress applied at the peak of plasma corticosterone. These differences in rates of decline of plasma ACTH or βEND/βLPH appear to reflect differences in secretion rate rather than clearance, since disappearance of [¹²⁵I]ACTH_1–24was not different after an initial vs. subsequent stress. In contrast to these data from intact rats, initial and subsequent stresses did not show different rates of decline of plasma ACTH or βEND/βLPH in adrenalectomized rats. In conclusion, the stress-induced rate rise of glucocorticoid provides a negative feedback signal which serves to terminate and limit the duration, but not the peak, of the responses of POMC-derived peptides to subsequent stress.

Footnotes

^* These studies were supported by Grants MT-5183 and MA-7000 from the Medical Research Council of Canada. Dr. De Souza was supported in part by the Alcoholism and Drug Addiction Research Foundation (Ontario) and in part by the University of Kentucky Department of Medicine Research and Education Fund.

Received July 12, 1989.

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