Brazilian Journal of Medical and Biological Research (2000) 33: 1121-1131 HPA axis in stress 1121 ISSN 0100-879X Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection S.M. McCann1, 1Pennington Biomedical Research Center (LSU), Baton Rouge, LA, USA J. Antunes-Rodrigues2, Departamentos de Fisiologia da 2Faculdade de Medicina e da C.R. Franci2, 3Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, J.A. Anselmo-Franci3, Ribeirão Preto, SP, Brasil S. Karanth1 and 4Centro de Estudios Farmacologicos y Botanicos, Consejo Nacional de Investigaciones V. Rettori4 Cientificas y Tecnicas (CEFYBO-CONICET), Buenos Aires, Argentina Abstract Correspondence The release of adrenocorticotropin (ACTH) from the corticotrophs is Key words S.M. McCann controlled principally by vasopressin and corticotropin-releasing hor- · Corticotropin-releasing Pennington Biomedical Research mone (CRH). Oxytocin may augment the release of ACTH under hormone (CRH) Center (LSU) · certain conditions, whereas atrial natriuretic peptide acts as a cortico- Vasopressin Baton Rouge, LA 70808-4124 · Oxytocin tropin release-inhibiting factor to inhibit ACTH release by direct USA · Atrial natriuretic peptide Fax: +1-225-763-3030 action on the pituitary. Glucocorticoids act on their receptors within (ANP) E-mail: [email protected] the hypothalamus and anterior pituitary gland to suppress the release · ACTH of vasopressin and CRH and the release of ACTH in response to these · Cortisol Presented at the First neuropeptides. CRH neurons in the paraventricular nucleus also project · Norepinephrine International Meeting on Adrenal to the cerebral cortex and subcortical regions and to the locus ceruleus · Acetyl choline Disease: Basic and Clinical (LC) in the brain stem. Cortical influences via the limbic system and · Nitric oxide Aspects, Ribeirão Preto, SP, Brazil, August 31-September 2, 1999. possibly the LC augment CRH release during emotional stress, whereas peripheral input by pain and other sensory impulses to the LC causes Research supported by the National stimulation of the noradrenergic neurons located there that project a Institutes of Health (Nos. DK43900 their axons to the CRH neurons stimulating them by -adrenergic and MH51853) to S.M. McCann. receptors. A muscarinic cholinergic receptor is interposed between the Publication supported by FAPESP. a-receptors and nitric oxidergic interneurons which release nitric oxide that activates CRH release by activation of cyclic guanosine monophosphate, cyclooxygenase, lipoxygenase and epoxygenase. Va- Received December 20, 1999 sopressin release during stress may be similarly mediated. Vaso- Accepted March 10, 2000 pressin augments the release of CRH from the hypothalamus and also augments the action of CRH on the pituitary. CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC noradrenergic neurons whose axons project to the paraventricular nucleus to augment the release of CRH. Introduction itary hormones. In the mid-1940s it was recognized that neural stimuli could evoke Dramatic progress has been made in pep- release of hormones from the anterior pitui- tide research over the last 45 years, and we tary. Examples included coitus-induced ovu- now know the specific hypothalamic pep- lation in birds, ferrets, cats, and other mam- tides that control the release of various pitu- mals, suckling-induced prolactin (PRL) re- Braz J Med Biol Res 33(10) 2000 1122 S.M. McCann et al. lease, and stress-induced release of adrenal mediately transplanted under the ME, so that corticotropic hormone (ACTH). One of the it was vascularized by the portal vessels, most important discoveries in the field was pituitary function returned to normal. A cor- that of the hypophyseal portal system of ollary of this experiment was carried out by veins by Popa and Fielding in 1933. These Nikovitch-Winer and Everett who showed originate from capillaries in the median emi- that pituitary grafts under the kidney capsule nence (ME), drain blood down the hypophy- did not sustain normal pituitary function but seal stalk, and supply the sinusoids of the later regrafting under the ME returned func- anterior lobe of the pituitary gland. Although tion to normal (for reviews, see Refs. 1 and blood flow was initially thought to be up- 2). ward in these vessels, Houssay and his col- leagues observed downward flow in the liv- Corticotropin-releasing factors ing toad in 1935. This observation was con- firmed in the living rat by Green and Harris The next logical step was to make ex- in 1947. It is apparent then that the primary tracts of the ME and to evaluate their effects flow is downward from the ME to the pitui- on pituitary hormone secretion. Because of tary; however, there is evidence that upward the early development of sensitive assays for flow may indeed occur under certain condi- determining ACTH release, attention first tions. focused on the ability of such extracts to In the meantime, it became apparent that evoke ACTH release. Because of the ready there was little if any functional innervation availability of partially purified extracts of to the anterior lobe, prompting a number of the posterior pituitary, which were used in workers to suggest that hypothalamic con- the preparation of commercial vasopressin trol over the pituitary might be mediated via (Pitressin) and oxytocin (Pitocin), these ex- neurohumoral agents released into the capil- tracts were tested in early experiments. To laries of the hypophyseal portal system that make extracts of the stalk ME required labo- would pass down the pituitary stalk and stimu- rious collection of the tissue at the slaughter- late the release of particular pituitary hor- house. The initial choice of posterior pitui- mones from the cells in the gland specialized tary extracts for testing was unfortunate but to produce each hormone. Indeed, deficits in led to the discovery of the ACTH-releasing pituitary hormone secretion followed lesions activity of vasopressin (3). Just after this, placed in various hypothalamic loci, and vasopressin was synthesized by Du Vigneaud conversely, electrical stimulation of these and colleagues (see Ref. 4), and the synthetic same regions was shown to evoke release of material was shown to be active in vivo to gonadotropins and ACTH. That the portal release ACTH in animals with ME lesions system was a crucial link between brain and that blocked the ubiquitous release of ACTH pituitary was suggested by the experiments from stress. It was reported that a substance of Harris and his collaborators who showed different from vasopressin could be isolated that following stalk section the portal vessels from posterior pituitary extracts that also frequently regenerated, and a return of nor- released ACTH; this substance was named mal pituitary function accompanied this re- corticotropin-releasing factor (CRF) (5,6). generation. On the other hand, a plate placed Early claims for a CRF other than vaso- between the cut ends of the stalk to block pressin in posterior pituitary extracts have such regeneration caused a permanent im- not been confirmed (7,8). Guillemin and pairment in pituitary function. In other ex- Schally even claimed to have partial struc- periments it was shown that if the pituitary tures of ß CRF and a I and II CRF. Again, was removed from its capsule and then im- these claims have not been confirmed (8). At Braz J Med Biol Res 33(10) 2000 HPA axis in stress 1123 this point in time, it is clear that there is such vasopressin antagonists (17). There are va- a factor in posterior lobe extracts; however, sopressin type II receptors similar to those in it is a minor contaminant and the major the vascular system on anterior pituitary ACTH-releasing activity of such extracts is corticotrophs that act to increase intracellu- accounted for by vasopressin (8,9). lar calcium in these cells (12), inducing a It was only when attention was turned to release of ACTH. On the other hand, CRH extracts of the stalk ME that it became clear acts on CRH type I receptors on the cortico- that indeed there was a separate corticotro- troph to activate adenylyl cyclase, leading to pin-releasing hormone (CRH) different from an increase in cyclic adenosine monophos- vasopressin (9). This material was purified phate (cAMP) that induces ACTH release and separated from vasopressin (10), but its (12). isolation and determination of structure An early candidate for CRF was epineph- proved difficult. In fact, although CRH was rine; however, its direct CRF activity ap- the first releasing factor to be discovered, it peared to be ruled out by the ability of ME was one of the last whose structure was lesions to block the response to epinephrine. elucidated, probably because it was a much This early concept is now reemerging in larger polypeptide. This feat was finally ac- view of the ability of epinephrine to evoke complished by Vale and Rivier and their ACTH release both in vivo and in vitro by an colleagues in 1981 (11). CRH turned out to action on ß-receptors which have been dis- be a 41-amino acid peptide, completely dis- covered in the gland. Epinephrine is released tinct from the octapeptide vasopressin, and during stress and could activate ACTH se- with no disulfide group in the molecule. cretion either by the increased concentra- It is now clear that vasopressin and CRH tions in the circulation or by its release into share physiological roles as CRFs. The vaso- portal blood, which would provide much pressin neuronal system has cell bodies pri- higher concentrations of the catecholamine. marily in the supraoptic nucleus (SON) but In fact, high concentrations of epinephrine also in the paraventricular nucleus (PVN) have recently been reported in portal blood. and axons that project primarily to the neural From all of this, it is apparent that there is no lobe; however, some of these axons, particu- single CRF.