Role of Corticotropin-Releasing Hormone in Gastrin-Releasing Peptide-Mediated Regulation of Corticotropin and Corticosterone Secretion in Male Rats

Abstract

Gastrin-releasing peptide (GRP) exerts several functions within the hypothalamus and may be involved in the regulation of pituitary hormone secretion. The purpose of this study was to investigate the central effect of GRP on hypothalamic-pituitary-adrenal axis activity in the male rat. Intracerebroventricular (i.c.v.) but not intravenous administration of GRP (1, 10, 100 ng/rat) increased plasma ACTH and corticosterone concentrations in a dose-dependent manner. The highest dose (100 ng/rat) of GRP increased plasma ACTH and corticosterone 4- and 14-fold, respectively. This increase peaked at 30–60 min after i.c.v. injection, decreased gradually and returned to baseline levels 240 min after GRP administration. The i.c.v. administration of (Leu¹³-ψ-CH₂NH-Leu¹⁴) bombesin, a competitive and specific GRP receptor antagonist, had no effect on ACTH and corticosterone secretion; however, a dose of 1 µg/rat completely blocked the increase of both hormones induced by GRP (10 ng). By using α-helical (9–41) corticotropin-releasing factor (CRF), a competitive antagonist of CRF, the role of CRF on GRP-induced ACTH and corticosterone secretion was also explored. α-Helical (9–41) CRF (10 µg/rat) blocked the increase in ACTH and corticosterone secretion induced by GRP (10 ng). The results obtained in this study suggest that GRP increases the secretion of ACTH and corticosterone in the plasma by acting centrally on GRP receptors, and that endogenous GRP receptor ligands do not tonically regulate ACTH and corticosterone secretion. Furthermore, the hypothalamus-pituitary-adrenal-activating effects induced by GRP appear to be mediated, at least in part, by CRF.

Central Bombesin Activates the Hypothalamic-Pituitary-Adrenal Axis

“…failed to engender endocrine variations (unpublished results). This is also congruent with the observation that central blockade of GRP (or BB 2 ) receptors attenuates stressor-elicited rise in ACTH and corticosterone [51]. …”

Role of bombesin-related peptides in the mediation or integration of the stress response

“…In addition, pretreatment with either CRH or AVP antisera blocked GRP-induced ACTH release by 60%, whereas pretreatment with combined antisera completely blocked this effect. It has also been shown that central administration of ah-CRF blocked the GRP-induced increase of ACTH and corticosterone [43]. In addition, in vitro evidence indicated that BN-LPs may be acting via CRH neurons.…”

“…Several laboratories, including ours, have shown that BN, along with its mammalian counterparts, GRP and NMB, can potently stimulate the release of ACTH from the anterior pituitary and corticosterone from the adrenal cortex [41 -47]. It is apparent that the ability of GRP to stimulate ACTH and corticosterone release is mediated via BB 2 receptors, as central administration of a competitive and specific BB 2 receptor antagonist completely blocked the GRP-induced increases in plasma ACTH and corticosterone levels [43]. The available data have been somewhat less consistent with respect to BN-induced endocrine effects following peripheral administration of the agonists.…”

“…The available data have been somewhat less consistent with respect to BN-induced endocrine effects following peripheral administration of the agonists. For instance, both Olsen et al [44] and Garrido et al [43] found that intravenous injection of GRP did not affect plasma ACTH or corticosterone levels in rats. In contrast, others reported that intravenous infusion or intraperitoneal administration of GRP or BN significantly elevated plasma ACTH and corticosterone levels in rats and dogs [48 -50].…”

“…It has been suggested that the discrepancies concerning the endocrine results following peripheral administration of BN-LPs may be related to species-dependent differences in sensitivities to BN-LPs, or differences in the dosages of BN-LPs utilized [44]. Indeed, in most studies where systemically administered BN-LPs have been found to stimulate ACTH and corticosterone (or cortisol) levels, the doses of the peptide(s) have typically been higher (> 2100 pmol) than in the studies where such a stimulatory effect was not seen (typically < 700 pmol) [43,44,48]. The inconsistent results obtained with systemic BN administration, as well as the need for relatively high doses of the peptide in order to provoke a stimulatory effect on ACTH or corticosterone secretion, has led to the suggestion that BN-LPs may be acting predominantly through central mechanisms at suprapituitary sites, such as the PVN or ME, to stimulate the HPA axis.…”