The oxytocinergic system in PTSD following traumatic childbirth: endogenous and exogenous oxytocin in the peripartum period.

Birth experiences can be traumatic and may give rise to PTSD following childbirth (PTSD-FC). Peripartum neurobiological alterations in the oxytocinergic system are highly relevant for postpartum maternal behavioral and affective adaptions like bonding and lactation but are also implicated in the response to traumatic events. Animal models demonstrated that peripartum stress impairs beneficial maternal postpartum behavior. Early postpartum activation of the oxytocinergic system may, however, reverse these effects and thereby prevent adverse long-term consequences for both mother and infant. In this narrative review, we discuss the impact of trauma and PTSD-FC on normal endogenous oxytocinergic system fluctuations in the peripartum period. We also specifically focus on the potential of exogenous oxytocin (OT) to prevent and treat PTSD-FC. No trials of exogenous OT after traumatic childbirth and PTSD-FC were available. Evidence from non-obstetric PTSD samples and from postpartum healthy or depressed samples implies restorative functional neuroanatomic and psychological effects of exogenous OT such as improved PTSD symptoms and better mother-to-infant bonding, decreased limbic activation, and restored responsiveness in dopaminergic reward regions. Adverse effects of intranasal OT on mood and the increased fear processing and reduced top-down control over amygdala activation in women with acute trauma exposure or postpartum depression, however, warrant cautionary use of intranasal OT. Observational and experimental studies into the role of the endogenous and exogenous oxytocinergic system in PTSD-FC are needed and should explore individual and situational circumstances, including level of acute distress, intrapartum exogenous OT exposure, or history of childhood trauma.

Inhaled oxytocin increases positive social behaviors in newborn macaques.

Early caregiver-infant interactions are critical for infants' socioemotional and cognitive development. Several hormones and neuromodulators, including oxytocin, affect these interactions. Exogenous oxytocin promotes social behaviors in several species, including human and nonhuman primates. Although exogenous oxytocin increases social function in adults--including expression recognition and affiliation--it is unknown whether oxytocin can increase social interactions in infants. We hypothesized that nebulized oxytocin would increase affiliative social behaviors and such effects would be modulated by infants' social skills, measured earlier in development. We also hypothesized that oxytocin's effects on social behaviors may be due to its anxiolytic effects. We tested these hypotheses in a blind study by nebulizing 7- to 14-d-old macaques (n = 28) with oxytocin or saline. Following oxytocin administration, infants' facial gesturing at a human caregiver increased, and infants' salivary oxytocin was positively correlated with the time spent in close proximity to a caregiver. Infants' imitative skill (measured earlier in development: 1-7 d of age) predicted oxytocin-associated increases in affiliative behaviors--lip smacking, visual attention to a caregiver, and time in close proximity to a caregiver--suggesting that infants with higher propensities for positive social interactions are more sensitive to exogenous oxytocin. Oxytocin also decreased salivary cortisol, but not stress-related behaviors (e.g., scratching), suggesting the possibility of some anxiolytic effects. To our knowledge, this study provides the first evidence that oxytocin increases positive social behaviors in newborns. This information is of critical importance for potential interventions aimed at ameliorating inadequate social behaviors in infants with higher likelihood of developing neurodevelopmental disorder.

Rapid Absorption of Dry-Powder Intranasal Oxytocin.

PURPOSE: To probe the suitability of a dry-powder oxytocin formulation containing a carrier (µco™; SNBL, Ltd.) for intranasal (IN) administration to treat post-partum hemorrhage in the developing world. Specifically, to investigate (1) whether IN administration can achieve rapid systemic absorption in cynomolgus monkeys, and (2) whether the formulation exhibits sufficient physical and chemical stability. This study was conducted to support Merck for Mothers, Merck's 10-year global initiative to end preventable maternal deaths. METHODS: A partial-crossover pharmacokinetic (PK) study in cynomolgus monkeys (n = 6) was utilized to compare in vivo absorption of dry-powder IN oxytocin at three dose levels against an IM injection of an aqueous oxytocin formulation. Particle size distribution, delivered dose and chemical assay were monitored over a 12 month stability study. RESULTS: IN administration of oxytocin resulted in short (5 min) Tmax and good dose linearity in AUC and Cmax over the dose range tested (10-80 IU per animal). The relative bioavailability (BA) of IN oxytocin to IM injection was approximately 12%. The 80 IU formulation exhibited good physical stability and consistent dosing. After 12 months at 30°C/65%RH, pouched samples retained 86.0% of their original assay value. CONCLUSIONS: The PK and stability data suggests that IN administration of oxytocin formulated in the µco™ carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design.

Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalata-kalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V1a receptors, members of the G protein-coupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.

[Oxytocin: the hormone of love, trust and social bond. Clinical use in autism and social phobia]. / L'ocytocine: hormone de l'amour, de la confiance et du lien conjugal et social.

Oxytocin, an octapeptide synthesized in the hypothalamus, stimulates milk election and uterine contractions. In the brain this hormone acts as a neuropeptide. It could inhibit through the GABAergic system the activity of limbic amygdala, which is involved in the response to fear. Oxytocin could also induce the protective behaviour of the mother towards its offspring through the dopaminergic system. In mankind, oxytocin plays a role in trust, empathy, generosity, stress and sexuality. Clinical studies are testing potential benefits of oxytocin administration in autism, depression and social phobia. Results are still preliminary.

Signaling Pathways Regulating Human Cervical Ripening in Preterm and Term Delivery.

At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process derivative of enzymatic breakdown and inflammatory response. Therefore, it is apparent that cervical remodeling is a derivative of the reactions mediated by multiple factors such as hormones, prostaglandins, nitric oxide, and inflammatory cytokines. However, despite the research carried out over the years, the cellular pathways responsible for regulating this process are still poorly understood. A comprehensive understanding of the entire process of cervical ripening seems crucial in the context of labor induction. Greater knowledge could provide us with the means to help women who suffer from dysfunctional labor. The overall objective of this review is to present the current understanding of cervical ripening in terms of molecular regulation and cell signaling.

Prostaglandin E2/EP1 signaling pathway enhances intercellular adhesion molecule 1 (ICAM-1) expression and cell motility in oral cancer cells.

Oral squamous cell carcinoma has a striking tendency to migrate and metastasize. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. However, the effects of COX-2 on human oral cancer cells are largely unknown. We found that overexpression of COX-2 or exogenous PGE(2) increased migration and intercellular adhesion molecule 1 (ICAM)-1 expression in human oral cancer cells. Using pharmacological inhibitors, activators, and genetic inhibition of EP receptors, we discovered that the EP1 receptor, but not other PGE receptors, is involved in PGE(2)-mediated cell migration and ICAM-1 expression. PGE(2)-mediated migration and ICAM-1 up-regulation were attenuated by inhibitors of protein kinase C (PKC)δ, and c-Src. Activation of the PKCδ, c-Src, and AP-1 signaling pathway occurred after PGE(2) treatment. PGE(2)-induced expression of ICAM-1 and migration activity were inhibited by a specific inhibitor, siRNA, and mutants of PKCδ, c-Src, and AP-1. In addition, migration-prone sublines demonstrated that cells with increased migration ability had higher expression of COX-2 and ICAM-1. Taken together, these results indicate that the PGE(2) and EP1 interaction enhanced migration of oral cancer cells through an increase in ICAM-1 production.

Prostaglandins in biofluids in pregnancy and labour: A systematic review.

Prostaglandins are thought to be important mediators in the initiation of human labour, however the evidence supporting this is not entirely clear. Determining how, and which, prostaglandins change during pregnancy and labour may provide insight into mechanisms governing labour initiation and the potential to predict timing of labour onset. The current study systematically searched the existing scientific literature to determine how biofluid levels of prostaglandins change throughout pregnancy before and during labour, and whether prostaglandins and/or their metabolites may be useful for prediction of labour. The databases EMBASE and MEDLINE were searched for English-language articles on prostaglandins measured in plasma, serum, amniotic fluid, or urine during pregnancy and/or spontaneous labour. Studies were assessed for quality and risk of bias and a qualitative summary of included studies was generated. Our review identified 83 studies published between 1968-2021 that met the inclusion criteria. As measured in amniotic fluid, levels of PGE2, along with PGF2α and its metabolite 13,14-dihydro-15-keto-PGF2α were reported higher in labour compared to non-labour. In blood, only 13,14-dihydro-15-keto-PGF2α was reported higher in labour. Additionally, PGF2α, PGF1α, and PGE2 were reported to increase in amniotic fluid as pregnancy progressed, though this pattern was not consistent in plasma. Overall, the evidence supporting changes in prostaglandin levels in these biofluids remains unclear. An important limitation is the lack of data on the complexity of the prostaglandin pathway outside of the PGE and PGF families. Future studies using new methodologies capable of co-assessing multiple prostaglandins and metabolites, in large, well-defined populations, will help provide more insight as to the identification of exactly which prostaglandins and/or metabolites consistently change with labour. Revisiting and revising our understanding of the prostaglandins may provide better targets for clinical monitoring of pregnancies. This study was supported by the Canadian Institutes of Health Research.

Interleukin-10 contributes to PGE2 signalling through upregulation of EP4 via SHIP1 and STAT3.

Macrophage cells form part of our first line defense against pathogens. Macrophages become activated by microbial products such as lipopolysaccharide (LPS) to produce inflammatory mediators, such as TNFα and other cytokines, which orchestrate the host defense against the pathogen. Once the pathogen has been eradicated, the activated macrophage must be appropriately deactivated or inflammatory diseases result. Interleukin-10 (IL10) is a key anti-inflammatory cytokine which deactivates the activated macrophage. The IL10 receptor (IL10R) signals through the Jak1/Tyk2 tyrosine kinases, STAT3 transcription factor and the SHIP1 inositol phosphatase. However, IL10 has also been described to induce the activation of the cyclic adenosine monophosphate (cAMP) regulated protein kinase A (PKA). We now report that IL10R signalling leads to STAT3/SHIP1 dependent expression of the EP4 receptor for prostaglandin E2 (PGE2). In macrophages, EP4 is a Gαs-protein coupled receptor that stimulates adenylate cyclase (AC) production of cAMP, leading to downstream activation of protein kinase A (PKA) and phosphorylation of the CREB transcription factor. IL10 induction of phospho-CREB and inhibition of LPS-induced phosphorylation of p85 PI3K and p70 S6 kinase required the presence of EP4. These data suggest that IL10R activation of STAT3/SHIP1 enhances EP4 expression, and that it is EP4 which activates cAMP-dependent signalling. The coordination between IL10R and EP4 signalling also provides an explanation for why cAMP elevating agents synergize with IL10 to elicit anti-inflammatory responses.

Oxytocin functions as a spatiotemporal filter for excitatory synaptic inputs to VTA dopamine neurons.

The experience of rewarding or aversive stimuli is encoded by distinct afferents to dopamine (DA) neurons of the ventral tegmental area (VTA). Several neuromodulatory systems including oxytocin regulate DA neuron excitability and synaptic transmission that process socially meaningful stimuli. We and others have recently characterized oxytocinergic modulation of activity in mouse VTA DA neurons, but the mechanisms underlying oxytocinergic modulation of synaptic transmission in DA neurons remain poorly understood. Here, we find that oxytocin application or optogenetic release decrease excitatory synaptic transmission, via long lasting, presynaptic, endocannabinoid-dependent mechanisms. Oxytocin modulation of excitatory transmission alters the magnitude of short and long-term depression. We find that only some glutamatergic projections to DA neurons express CB1 receptors. Optogenetic stimulation of three major VTA inputs demonstrates that oxytocin modulation is limited to projections that show evidence of CB1R transcripts. Thus, oxytocin gates information flow into reward circuits in a temporally selective and pathway-specific manner.

Maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) levels in post-term pregnancy: effect of prostaglandin administration.

OBJECTIVE: Placental corticotropin-releasing factor (CRF) affects myometrial contractility and the secretion of several uterotonins such as prostaglandins (PGs); however, the activity of CRF is counteracted by CRF-binding protein (CRF-BP). At term and pre-term labor, CRF levels in maternal plasma are highest whereas those of CRF-BP are falling, and the cause of this fall is unknown. Thus, in this study, we investigated the effect of PG administration for labor induction on maternal plasma CRF and CRF-BP concentrations. DESIGN: Maternal plasma CRF and CRF-BP levels were assayed before and after (2 h later) induction of labor by intracervical administration of prostaglandin E(2) (PGE(2)), and at delivery in a group of healthy post-term pregnancies (n=18). Controls were women at term out of labor (n=22), who subsequently progressed to deliver a healthy singleton baby. METHODS: CRF was measured by two-site immunoradiometric assay, and CRF-BP was assayed by radioimmunoassay. RESULTS: Maternal plasma CRF levels were significantly (P<0.0001) lower and CRF-BP significantly (P<0.0005) higher in post-term than in term pregnancies. With respect to induction of labor, 2 mg PGE(2) were sufficient to increase maternal plasma CRF levels at delivery (P<0.005). While 0.5 mg PGE(2) significantly decreased maternal plasma CRF-BP levels at delivery (P<0.001), 2.0 mg PGE(2) significantly reduced CRF-BP concentrations both after 2 h (P<0.05) and at delivery (P<0.0001). CONCLUSIONS: In the light of the well-known stimulation of prostaglandin release by CRF, these data suggest a positive feedback effect of PGE(2) on maternal CRF release during induced labor.

Oxytocin Experiments Shed Light on Mechanisms Shaping Prosocial and Antisocial Behaviors in Non-human Mammals.

Oxytocin has gained a reputation in popular culture as a simple "love drug" or "cuddle hormone", yet emerging biological evidence indicates that the effects of oxytocin are complex, mediating a suite of behavioral traits that range from ultrasocial to antisocial. Here we provide a comprehensive review to assess the salience of oxytocin in the lives of free-living social mammals. We reviewed the literature to understand the potential effects of oxytocin in promoting prosocial and antisocial behaviors in non-human mammals. Our review highlights a strong bias for studies of model organisms in highly-controlled settings, and emerging evidence for oxytocin's antisocial, context-specific and sex-specific effects. We discuss the results of the review in the context of insights gained from a pilot study aimed to investigate the potential for oxytocin to promote social cohesion in free-living yellow-bellied marmots (Marmota flaviventer). Our field experiment offers an example of the diverse issues that arise when conducting oxytocin manipulations in ecologically relevant contexts. Our synthesis highlights the challenges associated with acquiring adequate sample sizes for field-based, manipulative studies that require standardized measures of social behavior. Taken together, our findings lead us to join others in calling for revision of a simplistic view of oxytocin's role in regulating patterns of behavior. We draw from classical approaches used to study the mechanistic basis of behavior and offer a useful guide for disentangling these effects while appreciating the complex actions of oxytocin in shaping mammalian social behavior.

9alpha,11beta-PGF2 and its stereoisomer PGF2alpha are novel agonists of the chemoattractant receptor, CRTH2.

CRTH2 is a recently described chemoattractant receptor for the prostaglandin, PGD(2), expressed by Th2 cells, eosinophils and basophils, and believed to play a role in allergic inflammation. Here we describe the potency of several PGD(2) metabolites at the receptor to induce cell migration and activation. We report for the first time that the PGD(2) metabolite, 9alpha,11beta-PGF(2), and its stereoisomer, PGF(2alpha), are CRTH2 agonists. 9alpha,11beta-PGF(2) is a major metabolite produced in vivo following allergen challenge, whilst PGF(2alpha) is generated independently of PGD synthetase, with implications for CRTH2 signalling in the presence or absence of PGD(2) production.

Size-dependent increase in prostanoid levels in adenomas of patients with familial adenomatous polyposis.

Recent studies indicate that nonsteroidal anti-inflammatory drugs have a chemopreventive effect against colorectal neoplasia. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenases, principal enzymes that mediate the formation of prostanoids. To determine whether prostanoids are involved in the pathogenesis of colorectal adenomas, we compared the levels of five major stable metabolic products of the cyclooxygenase pathway in the normal-appearing mucosa and in adenomas of patients with familial adenomatosis polyposis. Of 12 patients tested, 6 had elevated levels of at least one prostanoid in the adenomas. More importantly, the relative levels of three prostanoids [prostaglandin (PG)D2, PGE2, and 6-keto-PGF1alpha] were elevated in adenomas compared to normal-appearing mucosa from the same patients, and the resulting ratios were correlated with the size of the adenoma. These results suggest a role for prostanoids in progression of colorectal polyposis in familial adenomatosis polyposis patients.

Oxytocin Protects against Stress-Induced Cell Death in Murine Pancreatic ß-Cells.

Oxytocin (Oxt) is a key neuropeptide that regulates maternal behaviors as well as social behaviors in mammals. Interestingly, recent studies have shown that the impairment of Oxt signaling is associated with the disturbance of metabolic homeostasis, resulting in obesity and diabetes. However, the molecular mechanism by which Oxt signaling controls metabolic responses is largely unknown. Here, we report that Oxt signaling attenuates the death of pancreatic beta cells in islets exposed to cytotoxic stresses. The protective effect of Oxt was diminished in islets isolated from oxytocin receptor knockout (Oxtr(-/-)) mice. Oxtr(-/-) mice developed normally, but exhibited impaired insulin secretion and showed glucose intolerance under a high-fat diet. Mechanistically, the deficiency of Oxtr impaired MAPK/ERK-CREB signaling, which exaggerated the endoplasmic reticulum stress response and ultimately increased the death of beta cells in pancreatic islets under stressed conditions. These results reveal that Oxt protects pancreatic beta cells against death caused by metabolic stress, and Oxt signaling may be a potential therapeutic target.

Cu(II) complexation does not affect oxytocin action on pregnant human myometrium in vitro.

OBJECTIVE: Copper may influence the in vivo and in vitro uterine activity. Recent evidence shows that cupric ions can easily form complexes with oligopeptides like oxytocin (OXT). The high complex stability in vitro suggests a possibility of complex formation in vivo. STUDY DESIGN: In vitro isometric contractions were recorded in uterine tissues from pregnant women undergoing caesarean sections and the effect of OXT and the Cu-OXT complex on isolated human pregnant myometrium was investigated. RESULTS: In the concentration range from 10(-14) to 10(-6)M of OXT alone, pre-formed Cu-OXT complex, and OXT following sample preincubation with Cu(II) salt, nosignificant differences were observed for the following parameters of pregnant uterine smooth muscle contraction: the area under the curve, frequency and amplitude of contraction. CONCLUSION: The binding of Cu(2+) ions does not abolish the ability of OXT to interact with oxytocin receptors and stimulate myometrial contraction in vitro.

IL-4 primes human endothelial cells for secondary responses to histamine.

Interleukin-4 (IL-4) is a multifunctional cytokine, which is involved in numerous disease states, including atopic asthma. IL-4 not only induces direct responses in cells but can also prime for secondary responses to stimuli. Little is known about the priming effects of IL-4 on endothelial cells; therefore, we chose to examine the ability of IL-4 to prime endothelial cells for platelet-activating factor (PAF) synthesis and prostaglandin E(2) (PGE(2)) release. IL-4 alone did not enhance PAF synthesis or PGE(2) release; however, pretreatment with IL-4 primed for PAF synthesis and PGE(2) release in response to subsequent stimulation with histamine. In contrast, tumor necrosis factor alpha (TNF-alpha), oncostatin M (OSM), and IL-1beta did not prime endothelial cells for PAF synthesis in response to histamine. The priming effects of IL-4 occurred without any detectable changes in the requirement for signaling pathways upstream of PGE(2) release. IL-4 treatment increased the expression of mRNA for histamine receptor 1 (HR1) and shifted the inhibition curve for pyrilamine, a specific HR1 antagonist. In addition, the dose-response curve for histamine-induced elevations in intracellular calcium was shifted following IL-4 stimulation. Together, these data indicate that HR1 is up-regulated in IL-4-stimulated human umbilical vein endothelial cells (HUVEC) and suggest that this up-regulation may contribute to the enhanced responsiveness of IL-4-stimulated HUVEC to histamine.

Corneal endothelial repair. Regulation of prostaglandin E2 synthesis.

PURPOSE: The authors have investigated the hypothesis that prostaglandin E2 (PGE2) synthesis is regulated during corneal endothelial wound healing. Previous studies have shown that PGE2 is an important mediator of endothelial mitosis, migration, and differentiation. METHODS: Biosynthesis of PGE2 was investigated in a wound closure model of the cultured rabbit corneal endothelium and in cultures treated with experimental agents. Prostaglandin E2 synthesis was measured by enzyme-linked immunosorbent assay. Pharmacologic experiments were designed to evaluate the contributions of protein kinases, phospholipase A2, and cyclooxygenase to endogenous PGE2 synthesis. RESULTS: Prostaglandin E2 synthesis is increased markedly in response to injury and is proportional to the extent of wounding. Biosynthesis of PGE2 returns to basal levels concurrently with recovery of the injury. Synthesis is dependent on the activities of protein kinase C (PKC), phospholipase A (PLA), and cyclooxygenase. Two forms of cyclooxygenase are present in corneal endothelial cells, and pharmacologic studies indicate that the activity of the COX 2 contributes to injury-dependent PGE2 synthesis. CONCLUSIONS: Prostaglandin E2 synthesis is increased in injured corneal endothelial cells. This synthesis is dependent on the coordinated regulation of PKC, PLA, and cyclooxygenase. Prostaglandin E2 synthesis presents an attractive target for pharmacologic manipulation of endothelial recovery from injury.