An Analogue of Met‐enkephalin Attenuates the Pituitary‐adrenal Response to Ovine Corticotrophin Releasing Factor

Grossman, Ashley; Delitala, G.; Mannelli, Michele; Al-Damluji, Saad; Coy, David H.; Besser, G. M.

doi:10.1111/j.1365-2265.1986.tb01708.x

Cited by 27 publications

(13 citation statements)

References 37 publications

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“…This hypothesis is also compatible with reports on the effects of morphine and DAMME on responses to either CRH-41 or vasopressin alone: DAMME and mor phine block the rise in cortisol induced by CRH-41 [29][30][31], while DAMME will inhibit the cortisol response to vasopressin [32]. On the current scheme, it is envisaged that exogenous opiate agonists inhibit both CRH-41 and vasopressin, hence, the response to either peptide would be suppressed by the ab sence of its synergising fetor.…”

Section: Discussionsupporting

confidence: 80%

Adrenergic Stimulation of the Human Pituitary-Adrenal Axis Is Attenuated by an Analog of Met-Enkephalin

et al. 1991

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It has previously been suggested that endogenous opioid peptides may suppress the pituitary-adrenal axis inhibiting an excitatory α₁-adrenoceptor input to neural mechanisms liberating corticotrophin-releasing factor or factc This hypothesis has been tested here by investigating the effect of the met-enkephalin analog, DAMME (FK-33,824), on the elevation in serum cortisol induced by the catecholamine-releasing agent d-amphetamine (10 and 25 mg p.o.) and α₁-adrenoceptor agonist methoxamine (6 µg/kg/min i.v.) in two groups of 6 normal male subjects. In both studies, serum cortisol was significantly attenuated by the analog of met-enkephalin. These data suggest that exogenous opioids downstream to the α₁-adrenoceptor input to CRF release; it appears that opioids modulate adrenocorticotrophic horm in man at a minimum of two distinct and separate sites.

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Section: Discussionsupporting

confidence: 80%

Adrenergic Stimulation of the Human Pituitary-Adrenal Axis Is Attenuated by an Analog of Met-Enkephalin

et al. 1991

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“…While there are some reports that have shown that loperamide poorly penetrates the blood-brain barrier [9,10], we have presented arguments for loperamide suppressing ACTH secretion in man by a possible suprapituitary site of ac tion, although an additional pituitary site could not be excluded [11]. These results parallel the findings obtained with a number of u-opiate agonists with regard to ACTH secretion in man [12][13][14],…”

Section: Introductionsupporting

confidence: 79%

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Auernhammer

Renner

Müller³

et al. 1993

Neuroendocrinology

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The effect of the antidiarrheal drug loperamide, a µ-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2–5 nM) and the membrane-permeable Bu(2)cAMP (0.5–2.5 mM). The protein kinase C pathway was stimulated with 1 µM arginine vaso-pressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 µM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 ± 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomela-nocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 µM). Morphine (0.01-10 µM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu₍₂₎cAMP-induced ACTH secretion in cell culture from 100 ± 4 to 77 ± 4% (p < 0.05). In Ca²⁺-depleted medium (Ca²⁺ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 ± 5 to 74 ± 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide. In comparison with the known effects of the calmodulin-inhibitors trifluoperazine, W-7 and penfluridol, loperamide mimicked all their effects on ACTH secretion. We conclude: (1) the effects of loperamide on corticotrophic cell function in vitro are naloxone-insensitive and not mediated by µ-opiate receptors; and (2) our data provide a strong argument for loperamide working as a calmodulin inhibitor in the rat anterior pituitary in vitro.

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“…The results of CRH studies indicate an inhibition of the first phase of the peptide after loperamide and resemble the findings obtained in normal subjects with CRH given after morphine [19] and after the met-enkephalin analog FK 33-824 [12], However, the present data do not agree with previous findings showing that, in normal subjects, FK 33-824 in duces an almost complete inhibition of ACTH secretion after LVP [6] and CRH [3[. These discrepancies may be ex plained by: (i) differences in the study protocol; (ii) a hig her sensitivity, in patients with Addison's disease to ACTH modulating agents, as a consequence of lacking cortisol feedback mechanism: (iii) the different properties of the opioids used: in fact, low doses of naloxone are able to re verse the effects of loperamide on ACTH secretion [4], while higher doses are required to counteract the inhibitory action of FK 33-824 [2],…”

Section: Discussionsupporting

confidence: 68%

“…Many in vitro [5,19] and in vivo studies [10,18] have indicated that opioids act at the hypo thalamic level, although an effect on pituitary corticotrophs has been also shown [14], In man, a direct influence on the pituitary gland has been hypothesized [6], while an interac tion of FK 33-824 [12] and morphine [19] with hypothalamic modulators of corticotropic secretion has been also sugges ted. The observation that loperamide is unable to suppress the ACTH responses after both CRH and vasopressin suggest a suprapituitary action.…”

Section: Discussionmentioning

confidence: 99%

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

1988

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Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison’s disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 µg/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 ± 17.3 to a peak of 95 + 21 pmol/l) and placebo (from 231 ± 59.5 to 365 ± 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 ± 16.6 to a peak of 108 ± 31 pmol/l) and placebo (from 98.5 ± 47 to 211 ± 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.

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An Analogue of Met‐enkephalin Attenuates the Pituitary‐adrenal Response to Ovine Corticotrophin Releasing Factor

Cited by 27 publications

References 37 publications

Adrenergic Stimulation of the Human Pituitary-Adrenal Axis Is Attenuated by an Analog of Met-Enkephalin

Adrenergic Stimulation of the Human Pituitary-Adrenal Axis Is Attenuated by an Analog of Met-Enkephalin

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

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