M. Ginsburg

THE EFFECTS OF OPIATE RECEPTOR AGONISTS AND ANTAGONISTS ON THE STRESS‐INDUCED SECRETION OF CORTICOSTERONE IN MICE

1 Intraperitoneal administration of normorphine, morphine or naloxone or exposure to ethervapour for 1 miri, elevated plasma corticosteroid concentrations in mice. 2 Injection of saline or exposure to ether vapour rendered mice less sensitive to a subsequent exposure to ether vapour 15 min later. 3 Treatment with normorphine (50 mg/kg) potentiated the corticosteroid response to ether stress whilst pentazocine (20 mg/kg), naltrexone (10 mg/kg), morphine (24 mg/kg), levorphanol (20 mg/kg) and naloxone (50 mg/kg) prevented the stress‐induced elevation of plasma corticosteroids. 4 Both naloxone and morphine inhibited the potentiation by normorphine of the response to ether, the dose of naloxone required being higher than that for inhibition of normorphine analgesia. 5 It is concluded that endogenous opioid peptides may be involved in the control of the response to ether stress in mice.

The specificity of oestrogen receptor in brain, pituitary and uterus.

1 The specificity of oestrogen receptor in rat brain regions (hypothalamus, amygdala and cortex), pituitary and uterus was studied by measurement of the inhibition of 17β‐oestradiol high affinity binding in cytosol, in the presence of unlabelled putative inhibitors of binding. 2 Binding was inhibited only by those of the compounds tested that possessed oestrogen agonist or antagonist activity. The affinities were estimated and the ranking order of the compounds was the same in all tissue sources of cytosol and corresponded to the ranking order of agonist or antagonist potency. 3 There were some significant differences between some of the estimated affinities in different tissues, these being seen most commonly between pituitary and hypothalamus on one hand and uterus on the other. 4 The possibility of heterogeneity of oestrogen receptor is discussed.

The effect of intracerebroventricular administration of methionine-enkephalin on the stress-induced secretion of corticosterone in mice.

Ether stress or intracerebroventricular (i.c.v.) administration of saline, met‐enkephalin, or naltrexone raised plasma corticosterone levels in mice. The response to ether stress was abolished by a preceding ether stress or by pretreatment. with i.c.v. saline or naltrexone. However, following i.c.v. met‐enkephalin, plasma corticosterone was significantly elevated by ether stress, the effect being blocked by simultaneous injection of met‐enkephalin and naltrexone. Met‐enkephalin appears to prevent fast‐feedback inhibition of the hypothalamus‐pituitary‐adrenal system.

Are there distinct dihydrotestosterone and testosterone receptors in brain

Abstract Investigations of cytosol receptor binding of androgen in brain have been carried out using either labelled testosterone or labelled dihydrotestosterone as ligand. The affinities of the binding of the ligands are in the same order of magnitude, competition shows that unlabelled excess of one can prevent binding of the other and both the testosterone and dihydrotestosterone high affinity binding moieties are rather uniformly distributed in brain. However, it is possible that these observations might conceal the existence of selective binding of one or other of the two ligands. Cytosols were prepared from brain and ventral prostate in adult male rats 2 days and 3 days after orchidectomy and from brain in intact adult females. In each cytosol the capacities and affinities of saturable, high affinity binding of both [ 3 H]-dihydrotestosterone were measured by Scatchard plot analysis. Twenty-one pairs of observations were made with brains from females and although the extreme differences in ligand binding capacities between pairs was about 5-fold, there was near perfect correspondence in estimates of the saturation capacities for the two ligands. Similarly, while the abundance of binding sites fell between the 2nd and 3rd day after orchidectomy (by 50% in brain and 80% in ventral prostate) the ratios of the saturation capacities were not significantly different from 1.0.

THE EFFECTS OF OPIOID DRUGS AND OF LITHIUM ON STEROIDOGENESIS IN RAT ADRENAL CELL SUSPENSIONS

1 The effects of opioid drugs and of Na+ replacement on steroidogenesis in rat adrenal cell suspensions were investigated. 2 In medium containing normal Na+ (156 mm), opioid antagonists but not opioid agonists reduced the steroidogenic response to adrenocorticotrophic hormone1–24. (ACTH1–24) but not to dibutyryl adenosine 3′,5′ cyclic monophosphate (db cyclic AMP). 3 Replacement of 50% Na+ in the medium by choline had no effect on steroidogenesis, but further reductions in Na+ content reduced the steroidogenic activity of both ACTH1–24 and db cyclic AMP. 4 In 50% Na+ medium both opioid agonists and antagonists inhibited ACTH1–24 induced steroidogenesis. 5 Addition of therapeutic concentrations of lithium to otherwise normal medium inhibited the steroidogenic response to ACTH1–24 but not to db cyclic AMP. 6 The selective inhibition of ACTH1–24‐induced steroidogenesis by opioid drugs suggests some similarity between the opioid and ACTH receptors. 7 The relevance of the potent inhibitory effect of lithium to its therapeutic actions is discussed.

Occurrence and properties of 17β-oestradiol receptors in rat brain

The occurrence and properties of 17beta-estradiol receptors in rat b rain are discussed. The numbers of 17beta-estradiol binding sites were measured separately in cytosols from anterior middle and posterior regions of the hypothalamus of adult rats in various states. The ratio of estrogen-specific high affinity binding site concentration in adult cortex-amygdada-hypothalamus was 1:5:11 in mixed cycling females and 1:3:6 in intact males. In 5-day-old rats the diethylstilbestrol (DES) suppressible binding sites were distributed in roughly equal concentration in both brain areas and at levels similar to those found in adult hypothalamus or amygdala. Equibibrium was reached in less than 5 minutes with uterine or hypothalamic cytosol whereas with pituitary cortex or amygdala more than 10 minutes were required. There was a difference in affinity between pituitary cytosol and cytosol from brain region or uterus. There was no difference in affinity between brain regions or between sexes in the neoates. It may be that the apparently lower affinities for estrone or 17beta-estradiol in the DES suppressible binding system is an artefact due to alpha-fetoprotein-like material in the incubates.

Effects of adrenalectomy and hypophysectomy on enkephalin content of the rat hypothalamus.

1 Hypothalamic content of enkephalin in rats has been measured by bioassay against methionine‐enkephalin on field‐stimulated mouse vas deferens after acid extraction and purification using Amberlite XAD‐2 resin. 2 Surgical stress lowered hypothalamic enkephalin content initially but 6 days after operation the content was higher in sham‐operated than in adrenalectomized animals. 3 Corticosteroid replacement therapy showed that hypothalamic enkephalin content was not related directly to circulating corticosteroid levels and that it was increased by the stress of handling and injection. 4 Hypothalamic enkephalin content of rats that had undergone hypophysectomy 11 days earlier did not differ from that of intact animals but surgical stress, which lowered content in intact rats and had no effect after adrenalectomy, produced a rise in content in these hypophysectomized animals. 5 The ingestion of 0.9% saline, in place of water, by sham‐adrenalectomized rats altered the effect of surgical stress on hypothalamic enkephalin content without affecting the resting levels. 6 Of extracts from adrenalectomized rats, 10% contained a substance that behaved atypically on the mouse vas deferens, showing a slower onset and offset of action. The mol. wt. of the substance and sensitivity to naloxone reversal appeared to be similar to enkephalin, but it was resistant to carboxypeptidase‐A and protease treatment. 7 It is concluded that the enkephalin content of the hypothalamus is affected by activity in the hypothalamus‐pituitary‐adrenal system but that it is not related in a simple manner to the levels of corticotrophin releasing hormone, corticotrophin or corticosteroids.