Elsevier

Peptides

Volume 19, Issue 5, May 1998, Pages 949-968
Peptides

Reviews
Role of Tachykinins in the Regulation of the Hypothalamo–Pituitary–Adrenal Axis

https://doi.org/10.1016/S0196-9781(98)00017-5Get rights and content

Abstract

Tachykinins are a family of neuropeptides, which act by binding to three main subtypes of G protein-coupled receptors, named NK1, NK2 and NK3. Tachykinins are contained in both nerve fibers and secretory cells of the hypothalamo—pituitary–adrenal (HPA) axis, and evidence indicates that they take part in the functional control of it. Tachykinins involved in this function include substance P (SP), neuropeptide K and its derivative neurokinin A (NKA), and neurokinin B, which preferentially bind to NK1, NK2 and NK3 receptors, respectively. NK1 agonists exert an inhibitory effect on the hypothalamo–pituitary CRH/ACTH system, while NK2 and perhaps NK3 agonists stimulate it, thereby controlling the secretion and growth of the adrenal cortex via circulating ACTH. Intra-adrenal tachykinins may also affect the cortex function. Their direct action on adrenocortical cells is doubtful and probably pharmacologic in nature, but several investigations suggest that tachykinins indirectly stimulate the cortex by acting on medullary chromaffin cells, which in turn exert a paracrine control on adrenocortical cells. SP enhances aldosterone production of zona glomerulosa by eliciting catecholamine secretion; neuropeptide K and NKA raise glucocorticoid production of zonae fasciculata and reticularis through the activation of the intramedullary CRH/ACTH system. The relevance of these effects of tachykinins under basal conditions is questionable, although there are indications that SP is involved in the maintenance of a normal growth and steroidogenic capacity of rat zona glomerulosa, and that SP and NKA play an important role in the stimulation of the adrenal growth during the fetal life. In contrast, evidence has been provided that the role of tachykinins, and especially of SP, could become very relevant under paraphysiological (e.g., physical or inflammatory stresses) or pathological conditions (e.g., ACTH-secreting pituitary tumors), when an excess of steroid-hormone production has to be counteracted.

Section snippets

Substance P

SP was first isolated from extracts of bovine hypothalamus and chemically characterized by Chang and Leeman [28]. Radioimmunoassay (RIA) and immunocytochemistry showed that SP is present throughout the CNS of mammals, although the hypothalamus is probably the region displaying the highest content. The SP distribution in the hypothalamus exhibits great variability among the various mammalian species 23, 40, 49, 50, 92, 93, 106, 107, 125, 130, 131, 178, 189, 208, 219.

The production of SP in the

Hypothalamus

Autoradiographic binding studies demonstrated the presence of abundant NK1 and NK3 receptor subtypes in the mammalian hypothalamus 12, 14, 23, 41, 42, 43, 147, 199, 209. Further studies showed that the distribution of NK1 and NK3 receptors in the rat hypothalamus is largely overlapped by that of their specific mRNAs 55, 134, 204. One exception is the parvocellular division of PVN, where, although NK3 mRNA is more abundant than NK1 mRNA, NK3 receptors are absent [204]. Moreover, despite the fact

Hypothalamic CRH and Arginine–Vasopressin (AVP) Secretion

Only scanty data are available on the direct effect of tachykinins on the hypothalamic CRH secretion. Faria et al. [60]reported that SP inhibits CRH release by rat hypothalamic tissue in vitro, while NKA is ineffective. In situ hybridization studies showed that SP decreases PPTA mRNA in the parvocellular subdivision of rat PVN [121], and the intraperitoneal (IP) administration of a specific NK1 receptor antagonist was found to raise both plasma ACTH concentration and CRH mRNA transcription in

Substance P

The acute bolus IP administration of SP, in a dose ranging from 50 to 100 μg/kg, was found to induce a net rise in aldosterone plasma concentration in rats, whose HPA axis and renin–angiotensin system had been pharmacologically interrupted to exclude any indirect action of the peptide via pituitary ACTH and angiotensin-II (ANG-II; [182]). Moreover, SP was shown to evoke a significant increase in the rate of aldosterone secretion by in situ perfused rat adrenals, minimal and maximal effective

Substance P

Despite its inhibitory action on the pituitary ACTH release, SP was not found to modify corticosterone blood levels in rats [182]. In contrast, SP infusion into men and women, at a rate of 1.5 pmol/kg·min, has been reported to raise cortisol levels in blood, a lower dose being ineffective 34, 35. Hinson et al. [85]observed that SP evokes a moderate increase in corticosterone output by in situ perfused rat adrenals, which is coupled with a 30% rise in the flow rate of the perfusion medium [82].

Steroid Secretion

The effects of tachykinins on non-mammalian corticosteroidogenesis have been studied exclusively in Amphibia, whose interrenal glands contain sizable levels of these peptides (see above). SP was found to raise corticosterone and aldosterone release from perifused adrenal tissue of Rana ridibunda [124]and Xenopus laevis [75], minimal and maximal effective concentrations being about 10−7M and 10−5M, respectively. Leboulenger et al. [124]also demonstrated that all other amphibian tachykinins

Cell Hypertrophy and Steroidogenic Capacity

The prolonged IP infusion of SP (50 μg/kg/h, for 7 days) has been reported to cause a sizable increase in the volume of rat ZG and its parenchymal cells and nuclei, as evaluated by morphometry. Stereological analysis of electron micrographs of ZG cells evidenced significant increases in the volumes of the mitochondrial compartment (20%) and smooth endoplasmatic reticulum (SER; 33%), along with a marked decrease in the volume of the lipid-droplet compartment (-43%). Zona fasciculata (ZF) and its

Stressful Conditions

As reviewed above, evidence has been provided that SP may be involved in limiting the exceedingly intense glucocorticoid secretory responses of rat adrenocortical cells to ACTH [141]. In agreement with these findings, Malendowicz et al. [143]showed that the NK1 antagonist spantide-II markedly enhances ACTH and corticosterone responses to ether-inhalation and cold stresses, without affecting the basal levels of these hormones. These authors concluded that SP probably plays a role in dampening

Concluding Remarks

The preceding sections of this survey have shown that a huge mass of data strongly suggests that tachykinins play a potentially important role in the paracrine regulation of the function of the HPA axis. The following conclusions can be drawn: 1) the NK1 agonists, like SP, exert both an inhibitory effect on the central branch of the CRH/ACTH system and a stimulatory effect specifically addressed to ZG and probably involving the stimulation of catecholamine release by chromaffin cells; 2) the

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