Role of tachykinins in the regulation of the hypothalamo-pituitary-adrenal axis.

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.