ReviewsRole of Tachykinins in the Regulation of the Hypothalamo–Pituitary–Adrenal Axis
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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2021, Molecular and Cellular EndocrinologyCitation Excerpt :The role of innervation in the regulation of adrenal steroidogenesis has been previously documented in several reviews (Whitworth et al., 2003; Ehrhart-Bornstein et al., 1998, 2000; Engeland, 2013). For instance, it has been reported that in rat, activity of sympathetic neurons enhances diurnal glucocorticoid secretion by increasing the adrenocortical cell responsiveness to ACTH (Engeland, 2013; Ulrich-Lai et al., 2006), whereas diverse neuropeptides including substance P, neuropeptide Y, neurotensin and Leu-enkephalin, stimulate aldosterone production (Hinson et al., 1994; Nussdorfer et al., 1988; Nussdorfer and Malendowicz, 1998). More recent studies have detailed the role of substance P, a neuropeptide belonging to the tachykinin family, in the human adrenal cortex (Wils et al., 2020).
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2013, Behavioural Brain ResearchCitation Excerpt :Like Ucn3, Tacr3 gene is also involved in neuroendocrine processes. For instance, it modulates GnRH (Gonadotropin releasing hormone) secretion from nerve terminals in the median eminence via NK3 receptors and regulates HPA-axis function [38–40]. Although functional studies are still scarce, it has been shown that administration of a NK3R antagonist reduced blood pressure in spontaneously hypertensive rats [41] and blocked cocaine-induced locomotor activity and anxiety behaviours in marmosets [42], while NK3 agonists stimulate HPA-axis function [39].
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2010, International Review of Cell and Molecular BiologyCitation Excerpt :Although ANP has been found not to affect cortisol secretion from dispersed guinea pig zona fasciculata-reticularis cells, a raise in cortisol production has been reported in guinea pig adrenocortical slices containing adrenomedullary tissue, suggesting an indirect effect, mediated by medullary chromaffin cells, under the secretagogue action of ANP (Raha et al., 2006). In fact, the bulk of evidence indicates that catecholamines are able to stimulate steroidogenesis through binding beta-adrenoreceptors on adrenocortical cells (Lightly et al., 1990; Mazzocchi et al., 1998; Nussdorfer, 1996) and various peptides, such as neuromedin U (Malendowicz et al., 1994, 2009), VIP and PACAP (Nussdorfer and Malendowicz, 1998a), neuropeptide-Y (Spinazzi et al., 2005), tachykinins (Nussdorfer and Malendowicz, 1998b), endothelins (Malendowicz et al., 1998; Nussdorfer et al., 1999), and adrenomedullin (Nussdorfer, 2001), have been found to stimulate cortisol secretion by indirect action on the medullary chromaffin cells. Lastly, in the evaluation of ANP effects on adrenal gland, relevant species-specific differences must be considered.