scholarly journals The importance of oxytocin mechanisms in the control of mouse parturition

Reproduction ◽  
2002 ◽  
pp. 543-552 ◽  
Author(s):  
AJ Douglas ◽  
G Leng ◽  
JA Russell
Keyword(s):  
Red Light ◽  
Endogenous Opioids ◽  
Beta Agonist ◽  
Early Gene ◽  
Opioid Antagonist ◽  
Dependent Manner ◽  
Birth Process ◽  
Opioid Agonist ◽  
Adrenergic Antagonist ◽  
Oxytocin Neurones

The role of oxytocin in parturition in mice was investigated. Pup birth profiles, blood samples and brains were collected from parturient mice observed under red light conditions in a reversed light:dark photoperiod. Peripheral administration of an oxytocin antagonist in a dose-dependent manner delayed the birth of subsequent pups, indicating that oxytocin is required for a normal pup birth profile. Oxytocin neurones were activated during birth as shown by both increased immediate early gene ( Fos) expression in oxytocin neurones in the supraoptic nucleus and increased plasma oxytocin concentrations during birth. In addition, the nucleus of the tractus solitarius and the olfactory bulbs, sites that process inputs to oxytocin neurones, become activated during parturition. Exposure to stress during parturition halted subsequent deliveries; at this stage plasma oxytocin concentrations were not higher than those of virgin mice, and birth was restored by administration of oxytocin. Administration of beta-adrenergic antagonist (propranolol) also restored stress-delayed birth, whereas administration of ritrodrine (beta-agonist) delayed birth in non-stressed mice, indicating that adrenergic mechanisms contribute to stress-delayed births in mice. Administration of morphine (mu-opioid agonist) delayed births transiently, but naloxone (opioid antagonist) did not prevent stress-delayed birth, indicating that endogenous opioids do not appear to contribute to neuroendocrine or uterine mechanisms that promote birth in mice. Therefore, despite evidence in oxytocin knockout mice that oxytocin is not essential for parturition in this species, the results of the present study indicate that oxytocin neurone activity and secretion contribute to the birth process in normal mice.

Effect of progesterone on the activation of neurones of the supraoptic nucleus during parturition

Reproduction ◽  
2000 ◽  
pp. 367-376 ◽  
Author(s):  
IA Antonijevic ◽  
JA Russell ◽  
RJ Bicknell ◽  
G Leng ◽  
AJ Douglas
Keyword(s):  
Progesterone Receptor ◽  
Supraoptic Nucleus ◽  
Late Pregnancy ◽  
Endogenous Opioids ◽  
Opioid Antagonist ◽  
Endogenous Opioid ◽  
Fos Expression ◽  
Oxytocin Neurones ◽  
Supraoptic Nuclei

Parturition is driven by a pulsatile pattern of oxytocin secretion, resulting from burst firing activity of supraoptic oxytocin neurones and reflected by induction of Fos expression. Rats were injected with progesterone on day 20 of pregnancy to investigate the role of the decreasing progesterone:ratio oestrogen ratio, which precedes delivery, in the activation of supraoptic neurones. Progesterone delayed the onset of birth by 28 h compared with vehicle (control) and prolonged the duration of delivery, which was overcome by pulsatile injections of oxytocin, indicating that the slow delivery may reflect impaired oxytocin secretion. Parturient rats pretreated with progesterone had fewer Fos immunoreactive nuclei in the supraoptic nucleus than did parturient rats pretreated with vehicle. The number of Fos immunoreactive nuclei was not restored after oxytocin injection, indicating that appropriate activation of oxytocin neurones is impaired by progesterone and also that there is a lack of stimulatory afferent drive. Fos expression increased in the nucleus of the tractus solitarius during parturition in rats pretreated with either vehicle or progesterone, but not in rats that had been pretreated with progesterone and induced with oxytocin, indicating that this input was inhibited. Endogenous opioids inhibit oxytocin neurones in late pregnancy and the opioid antagonist, naloxone, increases Fos expression in supraoptic nuclei by preventing inhibition. However, progesterone attenuated naloxone-induced Fos expression in the supraoptic nucleus in late pregnancy and naloxone administered during parturition did not accelerate the duration of births delayed by progesterone administration, indicating that progesterone does not act by hyperactivation of endogenous opioid tone. RU486, a progesterone receptor antagonist, enhanced supraoptic neurone Fos expression in late pregnancy, indicating progesterone receptor-mediated actions. Thus, progesterone withdrawal is necessary for appropriate activation of supraoptic and tractus solitarius neurones during parturition.

scholarly journals 11β-Hydroxysteroid Dehydrogenase Type 1 Induction in the Arcuate Nucleus by High-Fat Feeding: A Novel Constraint to Hyperphagia?

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4486-4495 ◽  
Author(s):  
Valerie S. Densmore ◽  
Nicholas M. Morton ◽  
John J. Mullins ◽  
Jonathan R. Seckl
Keyword(s):  
Arcuate Nucleus ◽  
Hydroxysteroid Dehydrogenase ◽  
Endogenous Opioids ◽  
Opioid Antagonist ◽  
Mrna Levels ◽  
High Fat ◽  
Opioid Agonist ◽  
The Metabolic Syndrome ◽  
Melanocortin 4 Receptor

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11β-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11β-HSD1 null (11β-HSD1−/−) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11β-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11β-HSD1−/− mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript and melanocortin-4 receptor, but higher levels of the orexigenic melanin-concentrating hormone mRNAs than controls (C57BL/6J) on a low-fat diet (11% fat). HF (58% fat) diet promoted transient (∼8 wk) hyperphagia and decreased food efficiency in 11β-HSD1−/− mice and decreased melanocortin-4 receptor mRNA expression in control but not 11β-HSD1−/− mice. 11β-HSD1−/− mice showed a HF-mediated up-regulation of the orexigenic agouti-related peptide (AGRP) mRNA in the arcuate nucleus which paralleled the transient HF hyperphagia. Conversely, control mice showed a rapid (48 h) HF-mediated increase in arcuate 11β-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected because glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial colocalization of 11β-HSD1 and AGRP in arcuate nucleus cells. One major alternate mechanism governing selective fat ingestion and the AGRP system is endogenous opioids. Treatment of HF-fed mice with the μ opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11β-HSD1−/− mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11β-HSD1. These data suggest that 11β-HSD1 in brain plays a role in the adaptive restraint of excess fat intake, in part by increasing inhibitory opioid tone on AGRP expression in the arcuate nucleus.

Opioid-induced regulation of µ-opioid receptor gene expression in the MCF-7 breast cancer cell line

2008 ◽  
Vol 86 (3) ◽  
pp. 217-226 ◽  
Author(s):  
Katarzyna Gach ◽  
Mariola Piestrzeniewicz ◽  
Jakub Fichna ◽  
Barbara Stefanska ◽  
Janusz Szemraj ◽  
...  
Keyword(s):  
Gene Expression ◽  
Opioid Receptor ◽  
Receptor Gene ◽  
Cancer Cell Line ◽  
Opioid Antagonist ◽  
Breast Adenocarcinoma ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Opioid Agonist ◽  
Mcf 7

The aim of the study was to investigate the presence of opioid receptor types in human breast adenocarcinoma MCF-7 cells and to characterize the changes in MOR expression induced by opioid agonist and antagonist treatment. We have shown that all three types of opioid receptors, but predominantly MOR, are expressed in MCF-7 cells. Selective MOR agonists, morphine, endomorphin-1, and endomorphin-2 downregulated MOR mRNA levels in a concentration- and time-dependent manner, but the effect produced by endomorphins was much stronger. Downregulation was blocked by the opioid antagonist naloxone. Naloxone alone produced a slight increase in MOR gene expression. Immunoblotting with antiserum against MOR-1 confirmed these results at the protein level. The results of our study indicate that, in MCF-7 cells, MOR gene expression is downregulated by opioid agonists and upregulated by opioid antagonists. We propose that the opioid-induced regulation of MOR mRNA expression is mediated by reduced binding of the transcription factors NFκB and AP-1 to the promoter region on the MOR gene.

Opioid growth factor inhibits DNA synthesis in mouse tongue epithelium in a circadian rhythm-dependent manner

1994 ◽  
Vol 267 (3) ◽  
pp. R645-R652 ◽  
Author(s):  
I. S. Zagon ◽  
Y. Wu ◽  
P. J. McLaughlin
Keyword(s):  
Circadian Rhythm ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Opioid Peptide ◽  
Endogenous Opioids ◽  
Opioid Antagonist ◽  
Dependent Manner ◽  
Endogenous Opioid ◽  
Endogenous Opioid Peptide ◽  
Opioid Growth Factor

In addition to neuromodulation, endogenous opioids also serve as growth factors. To investigate the involvement of the naturally occurring opioid peptide [Met5]enkephalin [termed opioid growth factor (OGF)] in the renewal of epithelium, adult mice were given systemic injections of OGF (1 mg/kg) and examined 2 h later at 0700 or 1700 h. DNA synthesis in the tongue was investigated using [3H]thymidine and autoradiography. OGF depressed DNA synthesis of the basal epithelial cells in the tip, and dorsal and ventral surfaces of the tongue (42-44% of control levels) only at 0700 h. This decrease in DNA synthesis was blocked by concomitant administration of the opioid antagonist naloxone (10 mg/kg); naloxone alone had no influence on cell replicative processes. Both OGF and its receptor, zeta (zeta), were detected in the stratified squamous epithelium of the ventral and dorsal surfaces of the tongue by immunocytochemistry. Photodensitometric measurements of immunocytochemical preparations revealed almost twofold more OGF and zeta-receptor immunoreactivity at 1700 h than at 0700 h. These results indicate that an endogenous opioid peptide and its receptor are present and govern cellular renewal processes in the tongue and regulate DNA synthesis in a circadian rhythm-dependent fashion.

Cardiovascular effects of opioid antagonist naloxone in rostral ventrolateral medulla of rabbits

1990 ◽  
Vol 258 (2) ◽  
pp. R325-R331 ◽  
Author(s):  
D. A. Morilak ◽  
G. Drolet ◽  
J. Chalmers
Keyword(s):  
Pressor Response ◽  
Cardiovascular Effects ◽  
Rostral Ventrolateral Medulla ◽  
Endogenous Opioids ◽  
Opioid Antagonist ◽  
Ventrolateral Medulla ◽  
Inhibitory Influence ◽  
Beneficial Effects ◽  
Arterial Blood ◽  
Depressor Effect

We have examined the influence of endogenous opioids on the basal and reflex control of arterial blood pressure in the pressor region of the rostral ventrolateral medulla (RVLM) of chloralose-anesthetized rabbits. We tested basal effects both in intact animals and after hypotensive hemorrhage. Bilateral administration of the opiod antagonist naloxone (20 nmol, 100 nl) directly into the RVLM induced a gradual and prolonged increase in mean arterial pressure (MAP) (+17 +/- 2 mmHg). This was preceded by a brief and mild depressor effect (-9 +/- 3 mmHg), which was attributable to a transient reduction in excitability immediately after naloxone injection. When naloxone was administered into the RVLM after hemorrhage (20 ml/kg), it improved recovery of MAP relative to saline controls, again producing a gradual, prolonged pressor response (+29 +/- 5 mmHg). The effect of naloxone on a baroreflex in intact animals was only transient, with a brief, nonsignificant attenuation of the reflex depressor response to aortic nerve stimulation. We conclude that endogenous opioids exert a tonic inhibitory influence on RVLM pressor neurons and that this input remains active after hemorrhage. The RVLM may thus be one site for the beneficial effects of naloxone in preventing circulatory decompensation after hemorrhage. In contrast, opioid neurons are not an essential component of baroreflex-mediated sympathoinhibition in the RVLM.

Abstract 2671: Thymosin Beta 4 Induced Oligodendrogenesis Is Associated With Upregulation Of Serum Response Factor

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Daniel C Morris ◽  
Benjamin Buller ◽  
Manoranjan Santra ◽  
Michael Chopp ◽  
Zheng Gang Zhang
Keyword(s):  
Western Blot ◽  
Progenitor Cells ◽  
Rat Model ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Embolic Stroke ◽  
Early Gene ◽  
Dependent Manner ◽  
Thymosin Beta 4 ◽  
Serum Response

Background: Thymosin beta 4 (Tβ4) is a G-actin sequestering peptide that improves neurological functional outcome when administered 24 hours after onset of stroke to a rat model of embolic stroke. Tβ4 increases the number of oligodendrocyte progenitor cells (OPCs) as well as mature oligodendrocytes (OLs). Mechanisms of Tβ4 induced oligodendrogenesis (OLG) remain unclear. Serum response growth factor (SRF) is a transcriptional factor which binds with ternary complex co-factors to primarily convey an immediate early gene response to influence and orchestrate neuronal migration and differentiation. Hypothesis: We tested the hypothesis that Tβ4 upregulates SRF with subsequent increase in the markers of OL differentiation. Results: We employed a mouse OPC line (N20.1) to investigate the mechanisms of Tβ4-induced OLG. The cells were plated at a density of 100,000 cells/ml and grown in the presence of 0, 12.5, 25 and 50 ng/ml of Tβ4 (RegeneRx Biopharmaceuticals, Inc.) for 14 days (n=3). Western blot analysis revealed that SRF was dose-dependently upregulated by a factor of 4. Quantitative real time PCR and Western blot analysis showed that Tβ4 treatment induced myelin basic protein (MBP) and 2’, 3’-cyclic nucleotide, 3’-phosphodiesterase (CNPase) expression in a dose-dependent manner by ∼2 fold, indicating the stimulation of OLG. In order to independently demonstrate that SRF promotes the differentiation of progenitor cells into mature oligodendrocytes, SRF was over expressed in the N20.1 cells using a plasmid encoding the SRF gene. After six days SRF over expressed N20.1 cells (n=3) demonstrated an increase of expression of MBP (26 ± 3%) and CNPase (23 ± 3%) when compared to cells transfected with an empty expression plasmid (n=3, MBP, 14 ± 3% and CNPase, 10 ± 4%, p<0.05). Conclusions: In this mouse model of OPCs, SRF was upregulated by Tβ4 and may be involved in Tβ4 induced OLG. Further in vivo investigation of SRF is warranted in our rat model of embolic stroke.

scholarly journals Modulation of High-Voltage Activated Ca2+ Channels in the Rat Periaqueductal Gray Neurons by μ-Type Opioid Agonist

1997 ◽  
Vol 77 (3) ◽  
pp. 1418-1424 ◽  
Author(s):  
Chang-Ju Kim ◽  
Jeong-Seop Rhee ◽  
Norio Akaike
Keyword(s):  
G Proteins ◽  
Opioid Receptor ◽  
High Voltage ◽  
Inhibitory Effect ◽  
Periaqueductal Gray ◽  
Dependent Manner ◽  
Opioid Agonist ◽  
Voltage Clamp Condition ◽  
Voltage Dependent ◽  
Clamp Condition

Kim, Chang-Ju, Jeong-Seop Rhee, and Norio Akaike. Modulation of high-voltage activated Ca2+ channels in the rat periaqueductal gray neurons by μ-type opioid agonist. J. Neurophysiol. 77: 1418–1424, 1997. The effect of μ-type opioid receptor agonist, D-Ala2,N-MePhe4,Gly5-ol-enkephalin (DAMGO), on high-voltage-activated (HVA) Ca2+ channels in the dissociated rat periaqueductal gray (PAG) neurons was investigated by the use of nystatin-perforated patch recording mode under voltage-clamp condition. Among 118 PAG neurons tested, the HVA Ca2+ channels of 38 neurons (32%) were inhibited by DAMGO (DAMGO-sensitive cells), and the other 80 neurons (68%) were not affected by DAMGO (DAMGO-insensitive cells). The N-, P-, L-, Q-, and R-type Ca2+ channel components in DAMGO-insensitive cells shared 26.9, 37.1, 22.3, 7.9, and 5.8%, respectively, of the total Ca2+ channel current. The channel components of DAMGO-sensitive cells were 45.6, 25.7, 21.7, 4.6, and 2.4%, respectively. The HVA Ca2+ current of DAMGO-sensitive neurons was inhibited by DAMGO in a concentration-, time-, and voltage-dependent manner. Application of ω-conotoxin-GVIA occluded the inhibitory effect of DAMGO ∼70%. So, HVA Ca2+ channels inhibited by DAMGO were mainly the N-type Ca2+ channels. The inhibitory effect of DAMGO on HVA Ca2+ channels was prevented almost completely by the pretreatment of pertussis toxin (PTX) for 8–10 h, suggesting that DAMGO modulation on N-type Ca2+ channels in rat PAG neurons is mediated by PTX-sensitive G proteins. These results indicate that μ-type opioid receptor modulates N-type HVA Ca2+ channels via PTX-sensitive G proteins in PAG neurons of rats.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus

2017 ◽  
Vol 46 (6) ◽  
pp. 450-458 ◽  
Author(s):  
Vandana S. Mathur ◽  
Jayant Kumar ◽  
Paul W. Crawford ◽  
Howard Hait ◽  
Thomas Sciascia ◽  
...  
Keyword(s):  
Rating Scale ◽  
Numerical Rating Scale ◽  
Controlled Trial ◽  
Hemodialysis Patients ◽  
Opioid Antagonist ◽  
Opioid Agonist ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Uremic Pruritus ◽  
The Mean

Background: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at μ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a μ-opioid antagonist and κ-opioid agonist. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. Results: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. Conclusions: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Development of Potent Bifunctional Endomorphin-2 Analogues with Mixed μ-/δ-Opioid Agonist and δ-Opioid Antagonist Properties

2004 ◽  
Vol 47 (14) ◽  
pp. 3591-3599 ◽  
Author(s):  
Yoshio Fujita ◽  
Yuko Tsuda ◽  
Tingyou Li ◽  
Takashi Motoyama ◽  
Motohiro Takahashi ◽  
...  
Keyword(s):  
Opioid Antagonist ◽  
Opioid Agonist

kappa-Opioid agonist inhibition of osmotically induced AVP release: preferential action at hypothalamic sites

1996 ◽  
Vol 270 (2) ◽  
pp. E367-E372 ◽  
Author(s):  
N. F. Rossi ◽  
D. P. Brooks
Keyword(s):  
Potent Inhibitor ◽  
Opiate Receptors ◽  
Opioid Antagonist ◽  
Posterior Pituitary ◽  
Opioid Agonist ◽  
Kappa Opioid ◽  
Water Diuresis ◽  
Kappa Agonist ◽  
Opioid Agonists ◽  
Kappa Opioid Agonist

Although several studies indicate that kappa-opioid agonists induce a water diuresis by inhibiting vasopressin (AVP) secretion, the locus of the kappa-receptors (neurohypophysial vs. hypothalamic) responsible for this effect remains unclear. We have ascertained the effect of the selective kappa-agonist BRL-52656 (BRL) on AVP secretion by using compartmentalized rat hypothalamoneurohypophysial explants in culture. When applied to the hypothalamus, nanomolar concentrations of BRL inhibited osmotically stimulated AVP secretion. This response was blocked by the highly selective kappa-opioid antagonist nor-binaltorphimine (BNI). However, osmotically stimulated AVP release was suppressed at the neurohypophysial site only by 100 nM BRL and was not reversed by BNI but only by naloxone. This dose of BRL, administered to the posterior pituitary compartment, did not appear to act by the agonist gaining access to hypothalamic kappa-opiate receptors, because BNI added to the hypothalamus failed to prevent the inhibition of AVP secretion. The data demonstrate that BRL is a potent inhibitor of osmotically stimulated AVP secretion via activation of kappa-opiate receptors within the hypothalamus, but that higher concentrations of the drug may also stimulate non-kappa-neurohypophysial opiate receptors that suppress AVP release.

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