Toshihiro Takao

Corticotropin-releasing hormone and pituitary-adrenocortical responses in chronically stressed rats

Brain corticotropin-releasing hormone (CRH) concentration and pituitary adreno-cortical responses were examined in chronically stressed rats: body restraint stress (6 h/day) for 4 or 5 weeks. Stressed rats showed a reduction in weight gain. CRH concentration in the median eminence and the rest of the hypothalamus were not different between control and chronically immobilized rats. The anterior pituitary adenocorticotropic hormone (ACTH) concentration was elevated in chronically stressed rats, whereas plasma ACTH and corticosterone levels did not differ from the control values. The median eminence CRH concentration was reduced to the same extent at 5 min after onset of ether exposure (1 min) in chronically immobilized rats and controls. However, plasma ACTH and corticosterone showed greater responses to ether stress in chronically immobilized rats than in control rats. Plasma ACTH and corticosterone responses to exogenous CRH were not different between control and chronically immobilized rats, while the response to arginine vasopressin (AVP) was significantly greater in chronically immobilized rats. These results suggest that chronic stress caused an increase in the ACTH-secreting mechanism and that pituitary hypersensitivity to vasopressin might at least be partly responsible for this.

Effect of atrial natriuretic peptide on acethylcholine-induced release of corticotropin-releasing factor from rat hypothalamus in vitro

Effect of rat atrial natriuretic peptide (rANP) on acetylcholine-induced release of corticotropin-releasing factor (CRF) from the rat hypothalamus was studied in vitro using perifusion method. Perifused acetylcholine at 100 and 1000 ng/ml evoked significant CRF release, whereas norepinephrine at 10, 100 and 1000 ng/ml did not show a definite effect on CRF release. Continuous administration of alpha-rANP(1-28) (20ng/ml) inhibited the acetylcholine (100ng/ml)-induced CRF release. It is likely that ANP is involved in the regulation of CRF release.

Central catecholaminergic control of ACTH secretion

Plasma adrenocorticotropic hormone (ACTH) has been measured after an intra-third ventricular administration of noradrenaline, an adrenergic agonist or an adrenergic antagonist. Centrally administered noradrenaline caused a significant increase in ACTH secretion. The alpha-agonist phenylephrine also increased the ACTH level. However, neither the alpha-antagonist phentolamine nor beta-agonist isoproterenol affected the ACTH level. The beta-antagonist propranolol evoked a significant elevation in ACTH. Passive immunoneutralization was examined with anti-rat corticotropin-releasing factor (CRF) rabbit serum, anti-arginine vasopressin (AVP) rabbit serum and normal rabbit serum (NRS) on the intra-third ventricular noradrenaline-induced ACTH secretion to study the involvement of endogenous CRF. An intra-third ventricular administration of noradrenaline caused a significant increase of ACTH levels in NRS-injected rats and anti-AVP-injected rats, whereas an i.v. anti-rat CRF injection significantly reduced the intra-third ventricular noradrenaline-induced ACTH secretion. These results suggest that central catecholamine stimulated ACTH secretion via the alpha-adrenergic mechanism and that endogenous CRF is at least partly involved in the noradrenaline-induced ACTH secretion.

Atrial natriuretic peptide does not affect corticotropin-releasing factor-, arginine vasopressin- and angiotensin II-induced adrenocorticotropic hormone release in vivo or in vitro

The effect of synthetic atrial natriuretic peptide (ANP) was examined on the in vivo and in vitro release of ACTH. Intravenous ANP (4 micrograms/kg body weight) administration did not affect the corticotropin releasing factor (CRF, 4 micrograms/kg body weight)-, arginine vasopressin (AVP, 2 micrograms/kg body weight)- and angiotensin II (A II, 4 micrograms/kg body weight)-induced ACTH release in unanesthetized freely moving rats. ANP did not inhibit the basal, CRF- and AVP-induced release of ACTH in pituitary cell cultures. ANP did not affect the CRF- and AVP-induced plasma corticosterone elevation, while it attenuated the AVP-induced corticosterone elevation. These results indicate that ANP does not affect the ACTH release at the pituitary level in vivo and in vitro.

Dual effects of (D-Ala2,Met5)-enkephalinamide on CRF and ACTH secretion

An intra-third ventricular administration of (D-Ala2,Met5)-enkephalinamide (DALA) did not elevate plasma ACTH and corticosterone levels in unanesthetized freely moving rats, but intra-third ventricular administration of DALA and methionine (Met)-enkephalin potentiated a mild stress (hanging for 10 or 30 sec)-induced plasma ACTH and corticosterone elevations in unanesthetized freely moving rats. DALA and Met-enkephalin seemed to stimulate CRF release from the median eminence to increase plasma ACTH, as the CRF concentration in the median eminence area was reduced after injection in these stressed rats. When hypothalamic tissues were perifused in vitro, DALA (1-100 ng/ml) reduced the release of CRF. These results suggest that the opiates seem to have a dual effect on the CRF-ACTH system depending on which action overrides the other.

Interleukin-1 Receptors in the Nervous System

The cytokine interleukin-1 (IL-1) is a hormone-like polypeptide that performs many roles in inflammation and immunity.1–3 Currently, two forms of IL-1 (IL-1α and IL-1β) and one IL-1 receptor antagonist (IL-1ra) have been characterized.1 In addition to its immune effects, a role has been postulated for IL-1 as a neurotransmitter/neuromodulator/growth factor in the central nervous system (CNS). IL-1 production has been reported in cultured brain astrocytes and microglia4–6 and IL-1 has been detected in the brain following cerebral trauma7,8 and endotoxin treatment.9 IL-1-like activity is also present in the cerebrospinal fluid (CSF),10,11 IL-1 mRNA is present in normal brain,12,13 and immunohistochemical studies have identified neurons positive for IL-1 β-like immunoreactivity in both hypothalamic14,15 and extrahypothalamic14 sites in human brain. Administration of IL-1 in brain produces a variety of effects, including induction of fever,1–3 alteration of slow-wave sleep,16,17 reduction of food intake,18 induction of analgesia,19 induction of acute-phase glycoprotein synthesis,20,21 stimulation of thermogenesis22,23 and reduction of peripheral cellular immune responses.24 Central as well as peripheral administration of IL-1 has potent neuroendocrine actions including stimulation of the hypothalamic-pituitary-adrenocortical axis25–27 and inhibition of the hypothalamic-pituitary-gonadal axis.28

Corticotrophin‐Releasing Factor Antagonist [alpha helical CRF(9–41)] Blocks Central Noradrenaline‐lnduced ACTH Secretion

Plasma ACTH increased after an intra‐third ventricular administration of noradrenaline (NA). An iv corticotrophin‐releasing factor (CRF) antagonist [alpha‐helical CRF(9–41)] injection did not affect ACTH secretion by itself, whereas it significantly reduced NA‐induced ACTH secretion. These results suggest that NA centrally stimulated ACTH secretion and that endogenous CRF is involved in this ACTH secretion.