Evidence for an interaction between α-MSH and opioids in the regulation of gonadotropin secretion in man

Limone, Paolo Piero; Calvelli, P; Altare, Frédéric; Ajmone-Catt, P.; Lima, Telmo Tiburcio Fortes; Gm, Molinatti

doi:10.1007/bf03346904

Cited by 22 publications

(13 citation statements)

References 21 publications

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“…This notion is supported by rat [19] and human [22,23] studies showing inhibition or stimulation of LH pulsatile secretion following administration of a melanocortin antagonist or agonist, respectively. We found that MTII acted much faster than leptin in restoring pulsatile LH secretion.…”

Section: Discussionsupporting

confidence: 53%

“…In support of this notion are the discoveries that almost all POMC cells in the ovine ARC express the leptin receptor ob/rb [5], and ovine POMC cells are activated following intravenous leptin injection (Clarke, unpublished data). Additionally, α-MSH [22] and γ-MSH [23] are capable of stimulating LH secretion in humans, and a central melanocortin receptor antagonist can reduce the effectiveness of leptin to restore gonadotropin secretion in starved rats [19]. It does, however, remain plausible that MTII elicits its effect independently of leptin signaling to rescue GnRH/LH secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Other work indicated that α-MSH [22] and γ-MSH [23] stimulate LH release in humans and that γ-MSH causes GnRH release from hypothalamic explants [23]. On the other hand, the MC3-R/MC4-R agonist melanotan II (MTII) had no effect on gonadotropin levels in male ob/obmice [24], suggesting a possible species difference.…”

Section: Introductionmentioning

confidence: 99%

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Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

et al. 2009

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Background/Aims: Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production. Methods and Results: Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of β-endorphin (β-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-α-MSH was the predominant form of α-melanocyte-stimulating hormone (α-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of α-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated α-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC. Conclusions: Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

et al. 2009

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“…Similar to CRF secretion, the hypothalamic hormone, gonadotropin releasing hormone (GnRH), is also modulated by inhibitory tone imposed by ␤-endorphin neu- rons (Limone et al 1997). By blocking inhibitory tone imposed by ␤-endorphin, Naloxone stimulates GnRH, which in turn stimulates LH secretion.…”

Section: Discussionmentioning

confidence: 99%

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Wand

2002

Neuropsychopharmacology

230

167

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An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor's extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the more commonStress threatens homeostasis and is counteracted by a series of physiological and behavioral responses that improve the chances for survival. A successful response to stress plays an important role in maintaining health and well-being. Abnormalities in the stress response heighten an individual's vulnerability to endocrine, metabolic, psychiatric, and immunological disorders (Kreek and Koob 1998; Bjorntorp and Rosmond 2000a,b;Chrousos 2000). The unique characteristics of an individual's stress response are the product of genetic and environmental determinants (Francis et al. 1999;Wust et al. 2000).Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al. 1998 (Wand et al. 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al. 1997;Wendel and Hoehe 1998). In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the common Asn40 variant and also induces a 3-fold increase in agonist-induced activation of G protein-coupled potassium channels (Bond et al. 1998). Because the Asn40Asp substitution alters receptor binding and signal transduction, it is plausible that this polymorphism alters processes under opioidergic regulation (LaForge et al. 2000a,b). The CRF neuron is also modulated by serotonergic fibers (Contesse et al. 2000;Isogawa et al. 2000). As opposed to ␤ -endorphin, which inhibits CRF secretion, serotonin activates the CRF neuron and stimulates CRF release. The serotonin transporter regulates the concentration of serotonin within the synaptic cleft and thereby modulates magnitude and duration of serotonin-induced postsynaptic mediated signals (Lesch and Mossner 1998). Recently a functional polymorphism has been described in the promoter region of the transporter, which modulates transcriptional activity of this gene as well as tissue expression of transporter activity (Hanna et al. 1998;Heils et al. 1997;Little et al. 1998). Like the A118G polymorphism in the mu-opioid receptor, it is plausible that this functional polymorphism within the serotonin transporter is associated with altered HPA axis dynamics.The present study was designed to test whether the Asn40Asp substitution polymorphism in the mu-opioid receptor or a functional mutation in the polymorphic region of serotonin transporter influences HPA axis activation induced by opioid receptor blockade. METHODS SubjectsHealthy men were recruited by newspaper from the Baltimore area. Respondents gave informed conse...

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“…The current observed increase in plasma testosterone is a surprising and unexpected finding. Some investigators have suggested a role for the melanocortins in the acute control of the gonadal axis (21,31,53); however, the agouti mice (2), the POMC KO mice (6), and the MC4-R KO mice (11) are all fertile, suggesting that the melanocortin system is not essential for reproduction. Our results support these findings.…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Small

Kim²,

Stanley³

et al. 2001

Diabetes

146

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The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...

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Evidence for an interaction between α-MSH and opioids in the regulation of gonadotropin secretion in man

Cited by 22 publications

References 21 publications

Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

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