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Department of Endocrinology, St Bartholomew's Hospital, London ec1a 7be received 16 February 1988 While stress and opiate alkaloids such as morphine have both been with us for millenia, the relationship between the two has remained obstinately enigmatic. The discovery of the endogenous opioid peptides some 13 years ago suggested that we might at last have found the key, but the partners to the relationship, while clearly well disposed to each other, persist in avoiding legal wedlock. Can we not find grounds at least for a prolonged engagement between stress and the opioids in current neuroendocrinology?
Introduction
Circulating opioid peptides
Endorphins
Measurement of circulating opioid peptides has certainly not been encouraging, following the initial euphoria in discovering that certain opioids were indeed present in the peripheral circulation. In man, β-lipotrophin (β-LPH) is co-released with adrenocorticotrophin (ACTH) after cleavage from pro-opiomelanocortin in the corticotrophs of the anterior pituitary,
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In the halcyon days when life was simple, many thought that pituitary hormones were under the control of single hypothalamic factors which regulated their synthesis and release. Matters became a little more complex when the search for growth hormone (GH)-releasing hormone was punctuated by the discoveries of somatostatin, which inhibited both GH and thyrotrophin (TSH), by the co-release of TSH and prolactin by thyrotrophin-releasing hormone, and then by the substantiation of other prolactin-releasing factors such as vasoactive intestinal peptide. It has since become increasingly clear that pituitary peptides are regulated by a whole series of hypothalamic factors, both stimulatory and inhibitory, and are also subject to intrapituitary paracrine modulation.
There has, however, been slow acceptance of the concept that the release of adrenocorticotrophin (ACTH) too may be finely tuned by an inhibitory factor. There is clearly a predominant role for a stimulatory factor to ACTH release, the earliest candidate for
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Introduction
A newly discovered class of messenger molecules appears to be concerned in a whole variety of biological functions in vertebrates: gaseous in nature, and thought of until recently as little more than toxic pollutants, these molecules have in fact become of considerable scientific importance. The notion of gases acting as biological signals was initially surprising, when it was proposed that nitric oxide (NO), or a closely related thiolic derivative, could account for the vasodilatory activity of endothelium-derived relaxing factor (EDRF) (Palmer et al. 1987). A rapidly growing body of evidence has since consistently indicated that NO or a related substance plays a role in such diverse functions as long-term potentiation (LTP), a neurophysiological model for the processes of learning and memory, as well as immune responses, and the autonomie activity underlying gut relaxation and penile erection subserved by non-adrenergic non-cholinergic (NANC) peripheral fibres (Moneada et al. 1991). Furthermore, there
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The response of LH from a perfused column of dispersed rat anterior pituitary cells to LH releasing hormone (LH-RH) and the analogue, d-Ser(But)6-desGly10-Proethylamide9-LH-RH (Hoe 766), was investigated. Dose–response curves showed non-parallelism between LH-RH and the analogue, but it was evident that the analogue was considerably more potent. After a single pulse of LH-RH, LH output returned to basal values in 8 min; this was prolonged to 20 min in the case of the analogue. During this 20 min the cells were refractory to pulses of LH-RH but pulses of the analogue maintained output of LH. During constant-dose perfusion with either synthetic LH-RH or the analogue, output of LH rapidly reached a peak and then gradually fell over several hours to approach baseline values. However, a pulse of 50 mmol potassium chloride/l was still able to release LH at this time. The data are consistent with the view that this analogue of LH-RH is highly potent and is strongly bound by the LH-RH receptor. Furthermore, since it desensitizes the LH-RH receptor, it appears that continued turnover of either LH-RH or the analogue at the receptor is necessary for output of LH to be maintained.
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Abstract
Bacterial lipopolysaccharide (LPS) and prostaglandins (PG) E2 and F2α are putative activators of the hypothalamo-pituitary-adrenal axis. Certain of the biological effects of LPS may be mediated by cytokines such as interleukin-1β (IL-1β), while IL-1β itself may operate via induction of the prostaglandins and/or nerve growth factor (NGF). As IL-1β stimulates the release of corticotrophin-releasing hormone (CRH) from acute rat hypothalamic explants directly, the effects of these substances on the release of CRH in vitro were investigated in short- and medium-term (20 and 60 min) incubations. The effect of LPS on the release of PGE2 and PGF2α from these explants, as well as from cortical astrocyte cultures, was also studied.
LPS did not modify the release of CRH, PGE2 or PGF2α in 20-min incubations. In 60-min incubations, LPS stimulated the release of PGE2, whereas the release of CRH was weakly, but significantly, reduced; PGF2α was not altered. PGE2 significantly stimulated CRH release in the 60-min but not in the 20-min experiments. This effect appeared to be selective for PGE2, since PGF2α did not modify CRH release, alone or in combination. LPS also selectively released PGE2 but not PGF2α from cortical astrocyte cultures after 24-h incubation. NGF had no effect on the release of explant CRH, regardless of the length of incubation.
It was concluded that neither LPS nor NGF acutely stimulate the hypothalamo-pituitary-adrenal axis by a direct action on hypothalamic CRH, while hypothalamic PGE2 may mediate, at least in part, certain of the neuroendocrine responses to LPS.
Journal of Endocrinology (1994) 140, 103–109
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ABSTRACT
Atrial natriuretic peptide, ANP(99–126), is derived from cardiac atrial tissue and has potent effects on salt and water homeostasis, including the inhibition of aldosterone and vasopressin release. Recent studies have also suggested that it may suppress the pituitary-adrenal axis. In addition, N-truncated forms of ANP, such as ANP(103–126), have been identified within the central nervous system, with a prominent hypothalamic localization in the paraventricular nucleus. We have therefore investigated whether ANP(99–126) and ANP(103–126) are able to modulate the release of the principal ACTH-releasing factor, corticotrophin-releasing factor-41 (CRF-41), from the rat hypothalamus in vitro.
The static incubation system has been previously described in detail. Male Wistar rats were decapitated between 09.00 and 09.30 h, their hypothalami rapidly removed, and four half-hypothalami incubated for 20-min intervals following a period of stabilization. The effect of the ANP peptides on the basal (B) and KCl (28 mmol/l)-stimulated (S) release of immuno-reactive CRF-41 was studied by means of successive incubations in the absence (B1, SI) and presence (B2, S2) of the peptides. The ratios B2: B1 and S2: S1 were compared with parallel control incubations by ANOVA.
Neither form of ANP had any effect on the basal release of CRF-41. ANP(99–126) caused a dose-dependent inhibition of CRF-41 release in the concentration range 1–100 nmol (P < 0·01). ANP(103–126) also suppressed the release of CRF-41 in the concentration range 100 pmol/l–100 nmol/l (P < 0·01), with a minimum S2:S1 ratio at 10 nmol/l, and a decrease in effect at 100 nmol/l. Finally, the stimulation of CRF-41 release induced by noradrenaline (10 nmol/l and 1 μmol/l) was non-competitively antagonized by 100 nmol ANP(99–126)/l and 10 nmol ANP(103–126)/l.
It was concluded that ANP may be an important regulator of the pituitary-adrenal axis by interaction with CRF-41. As there are data indicating that ANP may also directly inhibit the pituitary corticotroph, it would appear that central ANP is intimately involved in pituitary-adrenal function.
Journal of Endocrinology (1990) 126, 223–228
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Abstract
Opioid peptides are well established as potent inhibitors of the pituitary-adrenal axis, while α1-adrenoceptor drugs have recently been shown to stimulate this axis: both classes of agents appear to work principally above the level of the pituitary, most probable directly on the hypothalamus. There is also evidence that these drugs interact in their control of pituitary-adrenal function, although the specific hypothalamic releasing hormone involved has remained unclear. We have therefore carried out a study into the interaction of methoxamine, an α1-adrenoceptor agonist and naloxone, an opioid antagonist, together with human corticotrophin-releasing hormone (CRH), in a group of healthy volunteers in order to establish the mode of action of these drugs.
The following drugs were administered to a group of seven healthy male subjects in a randomized double-blind manner: methoxamine (6 μg/kg per min over 3 h); naloxone (10 mg bolus); human CRH (100 pg bolus); methoxamine plus CRH; naloxone plus CRH; methoxamine plus naloxone; saline (control). Plasma ACTH and serum cortisol were measured at intervals in each subject, and blood pressure and pulse rate recorded with each sample.
Both CRH and naloxone produce a marked rise in ACTH and cortisol, peaking at approximately 45 min after infusion. In combination, the drugs produced a peak response in plasma ACTH at the same time, but its magnitude was greater than that after either drug alone. Methoxamine produced a rise in plasma ACTH which was maximal at approximately 75 min, as well as a peak rise in serum cortisol at 120 min. This was greater than after either CRH or naloxone alone but, in combination, both drugs produced peak responses not significantly greater than when methoxamine alone was given.
While the interaction of drugs with differing pharmacokinetic profiles renders interpretation difficult, our data suggest that naloxone increases pituitary-adrenal activity via a mechanism independent of CRH, most probably hypothalamic vasopressin. This, albeit indirect, evidence suggests that α1-adrenoceptor activation with methoxamine activates hypothalamic pathways involving both endogenous CRH and vasopressin.
Journal of Endocrinology (1994) 141, 163–168
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ABSTRACT
Whilst it has been postulated that atrial natriuretic peptide (ANP) may modulate pituitary hormone release, several investigations in non-human species have reported conflicting results when looking for an effect on the hypothalamo-pituitary-adrenal axis. However, in a recent study significant inhibition of corticotrophin-releasing hormone (CRH)-stimulated ACTH in cultured rat anterior pituitary cells occurred only with the complete peptide α-ANP(1–28).
We have therefore investigated whether this form of ANP can inhibit CRH-stimulated ACTH and cortisol release in human subjects. Six healthy male volunteers received human α-ANP or placebo, and human CRH or placebo, on four separate occasions.
ANP was infused at a rate of 0·01 μg/kg per min in order to achieve levels in the high physiological range. CRH was given as a bolus dose of 100 μg 30 min into the ANP infusion. Cortisol and ANP were measured by radioimmunoassay, the latter after extraction. ACTH was measured by immunoradiometric assay. The data were analysed by Student's paired t-test on basal, peak and incremental levels. Basal levels of ANP were within the normal range (2–5 pmol/l). With ANP infusion, mean ± s.e.m. peak ANP levels were 29·6±3·1 pmol/l. There were no significant differences in mean basal cortisol and ACTH levels on each of the 4 study days. Mean peak cortisol and ACTH levels after CRH and ANP did not significantly differ from those achieved with CRH and placebo ANP. We thus conclude that at high physiological doses, circulating ANP does not inhibit CRH-stimulated ACTH or cortisol release.
Journal of Endocrinology (1991) 131, 163–167
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Linear bone growth depends upon proliferation, maturation, and apoptosis of growth plate chondrocytes, processes regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). To investigate the contribution of GH, IGF-I and apoptosis to growth plate function, the expression of GH receptor (GHR) and IGF-I receptor (IGF-IR) mRNA were evaluated by in situ hybridization in fractionated costochondral growth plates of growing rats (at 2, 4, and 7 weeks). Apoptosis was determined by TUNEL assay and morphology in histological sections. GHR mRNA was greatest in resting cells with hypertropic cells increasing GHR expression with increasing age. Hypertropic and resting cell IGF-IR mRNA declined over the ages studied. Receptor mRNA expression was altered by exposing cells to GH or IGF-I. GH and IGF significantly decreased GHR mRNA in proliferative cells. GH and IGF also decreased IGF-IR mRNA in resting cells and the 2- and 4-week-old proliferative and hypertropic cells. Treating cells in culture with GH increased the number of apoptotic cells across all ages and zones. Histologically, apoptotic cells were observed at the chondro-osseous junction and within actively proliferating chondrocytes but not in resting cells. Apoptosis was highest at 4 weeks of age with lateral regions displaying the greatest number of cells undergoing apoptosis. These data indicate that apoptosis plays a role in growth plate function, particularly spatial configuration as indicated by the preferential lateral cell apoptosis. The susceptibility of proliferative cells to GHR and IGF-IR down regulation during the period of greatest apoptosis supports a role for the GH–IGF axis in both proliferation and apoptosis during growth plate development.
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ABSTRACT
Secretion of GH in the rat has been shown to be dependent upon age and sex. Using rat hypothalamic explants in vitro, we have studied the release and hypothalamic content of GH-releasing hormone (GHRH) and somatostatin in male and female Wistar rats at four different ages (10, 30 and 75 days, and 14 months). Basal release of GHRH was not significantly different between male and female rats, but at all ages males released more GHRH in response to stimulation by both 28 and 56 mmol potassium/l than female rats (P<0·05). Neither basal nor potassium-stimulated release of GHRH altered with age. In contrast, both basal and potassium-stimulated secretion of somatostatin increased significantly (P<0·01) with age, but was the same in the two sexes. Hypothalamic GHRH content, as assessed by the extractable tissue content following incubation, was significantly (P<0·01) lower in 10-day-old rats compared with older rats, but remained constant after 30 days of age. Somatostatin content, in contrast, increased progressively with age (P<0·01). The hypothalamic content of the two peptides was the same in both sexes.
In conclusion, our findings demonstrate that male rats release more GHRH in vitro than female rats, possibly reflecting the increased pulse amplitude of GH seen in males in vivo; the progressive fall in secretion of GH previously reported during ageing appears to parallel the progressive increase in somatostatin release and content seen in our in-vitro system.
Journal of Endocrinology (1989) 123, 53–58
