Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides.

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed.

Oxytocin receptor antagonist reverses the blunting effect of pair bonding on fear learning in monogamous prairie voles.

Social relationships among spouses, family members, and friends are known to affect physical and mental health. In particular, long-lasting bonds between socio-sexual partners have profound effects on cognitive, social, emotional, and physical well-being. We have previously reported that pair bonding in monogamous prairie voles (Microtus ochrogaster) is prevented by a single prolonged stress (SPS) paradigm, which causes behavioral and endocrine symptoms resembling post-traumatic stress disorder (PTSD) patients in rats (Arai et al., 2016). Since fear memory function is crucial for anxiety-related disorders such as PTSD, we investigated the effects of pair bonding on fear learning in prairie voles. We applied an SPS paradigm to male prairie voles after the cohabitation with a male (cage-mate group) or female (pair-bonded group). The cage-mate group, but not the pair-bonded group, showed enhanced fear response in a contextual fear conditioning test following the SPS treatment. Immunohistochemical analyses revealed that cFos-positive cells in the central amygdala were increased in the pair-bonded group after the contextual fear conditioning test and that oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus was significantly higher in the pair-bonded group than the cage-mate group. This pair-bonding dependent blunting of fear memory response was confirmed by a passive avoidance test, another fear-based learning test. Interestingly, intracerebroventricular injection of an oxytocin receptor antagonist 30 min before the passive avoidance test blocked the blunting effect of pair bonding on fear learning. Thus, pair bonding between socio-sexual partners results in social buffering in the absence of the partner, blunting fear learning, which may be mediated by oxytocin signaling.

Central oxytocin alters cortisol and behavioral responses of guinea pig pups during isolation in a novel environment.

The neuropeptide oxytocin plays key roles in social bonding and stress reduction, and thus appears to be a likely mediator of maternal buffering of infant stress responses. In the guinea pig, the presence of the mother in a threatening environment buffers cortisol elevations as well as active (vocalizing) and passive (e.g. crouching) responses typical of isolation in this species; yet, effects of OT in guinea pig pups under any conditions have not been reported. Here, we examined the ability of intracerebroventricular (ICV) OT to moderate plasma cortisol levels and behavior in guinea pig pups isolated in a brightly lit, novel environment, and the ability of a highly selective OT antagonist (OTA) to reduce buffering by the mother. We found that ICV OT moderated cortisol levels and vocalizations, but increased time spent in the crouched stance, particularly in females. In addition, OT modulated other ongoing behaviors in a sex-dependent fashion. In females, OT reduced duration of walking and rearing, and increased time spent quiet, while in males OT increased duration of rearing. OTA, however, was without effect on cortisol levels or behavior. These findings, including sex differences in response, extend results from other species to the guinea pig. Further, while demonstrating that exogenous OT is sufficient to reduce biobehavioral stress responses typical of isolated guinea pig infants, the results suggest that endogenous OT is not necessary for maternal buffering of infant responses in this species.

The role of the vasopressin V1A receptor in oxytocin modulation of methamphetamine primed reinstatement.

The neuropeptide oxytocin has shown promise as an effective therapy in pre-clinical models of methamphetamine (METH) addiction. The nucleus accumbens core (NAcc) has been identified as an important site for oxytocin to inhibit METH behaviours, although previous findings suggest that the effects of oxytocin in the NAcc are mediated by receptors other than the oxytocin receptor (OTR). Oxytocin has high affinity for the vasopressin V1A receptor (V1AR) which has been implicated in numerous oxytocin-dependent social behaviours. The aim of this study was to investigate the involvement of the V1AR in mediating the effect of oxytocin treatment to reduce METH-primed reinstatement of METH-seeking behaviour. Male rats were trained to self-administer intravenous infusions of METH by lever press during daily 2-h fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever pressing, rats were tested for the effects of oxytocin alone, oxytocin co-administered with a selective V1AR antagonist, or oxytocin co-administered with a selective OTR antagonist, on METH-primed reinstatement, when administered systemically, or when microinjected into the NAcc. Systemic administration of oxytocin prevented METH-primed reinstatement, an effect which was significantly reduced by systemic pre-treatment with a V1AR but not OTR antagonist. Local administration of oxytocin into the NAcc reduced METH-primed reinstatement, but not when the V1AR was blocked. Our results demonstrate a substantial role for the V1AR in mediating the inhibitory effects of oxytocin on METH-primed reinstatement, and indicate the need for investigations into the differential involvement of V1ARs and OTRs in oxytocin-induced reduction of METH-related behaviours.

New Approach to Calculation of Renal Cation Clearance in Rats after V1a Receptor Stimulation.

V1a receptor agonist [Phe2, Ile3, Orn8]-vasopressin produces maximum diuretic and saluretic effects in a dose of 0.1 nmol/100 g body weight: renal excretion of Na+ increases by 50 times in comparison with the initial level over 90 min, excretion of K+, Mg2+, and Са2+ increases by 3, 2, and 16 times, respectively. New formulas were proposed for calculation of the clearance considering total cation content in the extracellular fluid and the time of total effect of the injected dose. After injection of V1a receptors agonist, clearance of Na+ was 7% of its total content in the extracellular fluid, the corresponding values for K+, Mg2+, and Ca2+ were 63, 35, and 6%, respectively. The proposed approach differs significantly from the standard cation excretion evaluation and characterizes selective shifts in ion balance induced by physiologically active substances and possible side effects due to unbalanced loss of certain ions.

Seasonal Variation in Group Size Is Related to Seasonal Variation in Neuropeptide Receptor Density.

In many species, seasonal variation in grouping behavior is widespread, with shifts towards territoriality in the breeding season and grouping in the winter. Compared to the hormonal and neural mechanisms of seasonal territorial aggression, the mechanisms that promote seasonal grouping have received little attention. We collected brains in spring and winter from wild-caught males of two species of emberizid sparrows that seasonally flock (the field sparrow, Spizella pusilla, and the dark-eyed junco, Junco hyemalis) and two species that do not seasonally flock (the song sparrow, Melospiza melodia, and the eastern towhee, Pipilo erythrophthalmus). We used receptor autoradiography to quantify seasonal plasticity in available binding sites for three neuropeptides known to influence social behavior. We examined binding sites for 125I-vasoactive intestinal polypeptide (VIP), 125I-sauvagine (SG, a ligand for corticotropin-releasing hormone receptors) and 125I-ornithine vasotocin analog (OVTA, a ligand for the VT3 nonapeptide). For all species and ligands, brain areas that exhibited a seasonal pattern in binding density were characterized by a winter increase. Compared to nonflocking species, seasonally flocking species showed different binding patterns in multiple brain areas. Furthermore, we found that winter flocking was associated with elevated winter 125I-VIP binding density in the medial amygdala, as well as 125I-VIP and 125I-OVTA binding density in the rostral arcopallium. While the functional significance of the avian rostral arcopallium is unclear, it may incorporate parts of the pallial amygdala. Our results point to this previously undescribed area as a likely hot spot of social modulation.

Effect of vaginal infiltration with ornipressin or saline on intraoperative blood loss during vaginal prolapse surgery: a randomised controlled trial.

INTRODUCTION AND HYPOTHESIS: Hydrodissection incorporating different types of vasoconstrictors is commonly used in vaginal prolapse surgery. There is little evidence as to whether it adds clinical value or whether it exposes the patient to unnecessary risk. The aim of this study was to compare the effect of a vasoconstrictor compared with saline alone on operative blood loss and cardiovascular parameters in a randomised clinical trial setting. METHODS: Patients undergoing vaginal prolapse surgery were randomised to an ornipressin (Por-8, Ferring) solution or saline alone for hydrodissection. The surgeon and patient were blinded to the solution used. Operative blood loss was accurately quantified and blood pressure and pulse readings recorded Pre, intra- and postoperatively. RESULTS: Eighty women were randomised. There was a statistically significant difference in the median blood loss: 35 ml (1-209 ml) in the ornipressin group compared with 81 ml (2-328 ml) in the saline group, p = 0.03. There was no statistically significant difference in the median pre and postoperative blood pressure or pulse rate between groups. CONCLUSIONS: The use of a vasoconstrictor (ornipressin) resulted in a statistically significant decrease in operative blood loss during vaginal prolapse surgery. This occurred without any significant changes in measured cardiovascular parameters.

Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition.

Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 µl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 µl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition.

Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum.

Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.

Social preference and maternal defeat-induced social avoidance in virgin female rats: sex differences in involvement of brain oxytocin and vasopressin.

BACKGROUND: Research concerning non-reproductive sociability in rodents is mainly restricted to assessing the effects of oxytocin (OXT) and arginine-vasopressin (AVP) in male rats and mice. Comparable studies on natural social preference and social avoidance in females are substantially lacking. NEW METHOD: Here, we adapted a behavioral paradigm for monitoring social preference of female rats consisting of two consecutive exposures to either non-social or social stimuli. Further, to induce stimulus-specific social avoidance, female rats were exposed to a single 10-min maternal defeat by a lactating dam. RESULTS: Social preference towards same-sex conspecifics in female rats was shown to be independent of the estrous cycle and even more pronounced than in male rats. Intracerebroventricular (icv) application of OXT, AVP, or their selective receptor antagonists or agonists, did not alter naturally-occurring social preference in female rats. Stimulus-specific social avoidance could be induced by prior exposure to a lactating rat: an effect that could not be reversed/overcome by icv OXT. COMPARISON WITH EXISTING METHOD(S): The female social preference paradigm for rats established in this study detected subtle sex differences in social preference behavior of rats. Further, stimulus-specific social deficits could be induced in female rats using an acute exposure to social defeat - as previously observed in male rodents. CONCLUSIONS: Female rats show strong social preference behavior, which can be prevented by social defeat, but does not seem to be regulated by the OXT or AVP systems. Accordingly, icv application of synthetic OXT does not reverse maternal defeat-induced social avoidance in female rats.

Estrogen receptor ß and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats.

The hypothalamic-pituitary-adrenal (HPA) axis is activated in response to stressors and is controlled by neurons residing in the paraventricular nucleus of the hypothalamus (PVN). Although gonadal steroid hormones can influence HPA reactivity to stressors, the exact mechanism of action is not fully understood. It is known, however, that estrogen receptor ß (ERß) inhibits HPA reactivity and decreases anxiety-like behavior in rodents. Since ERß is co-expressed with oxytocin (OT) in neurons of the PVN, an ERß-selective agonist was utilized to test the whether ERß decreases stress-induced HPA reactivity and anxiety-like behaviors via an OTergic pathway. Adult gonadectomized male and female rats were administered diarylpropionitrile, or vehicle, peripherally for 5days. When tested for anxiety-like behavior on the elevated plus maze (EPM), diarylpropionitrile-treated males and females significantly increased time on the open arm of the EPM compared to vehicle controls indicating that ERß reduces anxiety-like behaviors. One week after behavioral evaluation, rats were subjected to a 20minute restraint stress. Treatment with diarylpropionitrile reduced CORT and ACTH responses in both males and females. Subsequently, another group of animals was implanted with cannulae directed at the lateral ventricle. One week later, rats underwent the same protocol as above but with the additional treatment of intracerebroventricular infusion with an OT antagonist (des Gly-NH2 d(CH2)5 [Tyr(Me)(2), Thr(4)] OVT) or VEH, 20min prior to behavioral evaluation. OT antagonist treatment blocked the effects of diarylpropionitrile on the display of anxiety-like behaviors and plasma CORT levels. These data indicate that ERß and OT interact to modulate the HPA reactivity and the display of anxiety-like behaviors.

Sex-specific activity and function of hypothalamic nonapeptide neurons during nest-building in zebra finches.

Vertebrate species from fish to humans engage in a complex set of preparatory behaviors referred to as nesting; yet despite its phylogenetic ubiquity, the physiological and neural mechanisms that underlie nesting are not well known. We here test the hypothesis that nesting behavior is influenced by the vasopressin-oxytocin (VP-OT) peptides, based upon the roles they play in parental behavior in mammals. We quantified nesting behavior in male and female zebra finches following both peripheral and central administrations of OT and V1a receptor (OTR and V1aR, respectively) antagonists. Peripheral injections of the OTR antagonist profoundly reduce nesting behavior in females, but not males, whereas comparable injections of V1aR antagonist produce relatively modest effects in both sexes. However, central antagonist infusions produce no effects on nesting, and OTR antagonist injections into the breast produce significantly weaker effects than those into the inguinal area, suggesting that antagonist effects are mediated peripherally, likely via the oviduct. Finally, immunocytochemistry was used to quantify nesting-induced Fos activation of nonapeptide neurons in the paraventricular and supraoptic nuclei of the hypothalamus and the medial bed nucleus of the stria terminalis. Nest-building induced Fos expression within paraventricular VP neurons of females but not males. Because the avian forms of OT (Ile(8)-OT; mesotocin) and VP (Ile(3)-VP; vasotocin) exhibit high affinity for the avian OTR, and because both peptide forms modulate uterine contractility, we hypothesize that nesting-related stimuli induce peptide release from paraventricular vasotocin neurons, which then promote female nesting via peripheral feedback from OTR binding in the oviduct uterus.

Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics.

Brain oxytocin (OXT) plays an important role in short-term social memory in laboratory rodents. Here we monitored local release of OXT and its functional involvement in the maintenance and retrieval of social memory during the social discrimination test. We further assessed, if the local effects of OXT within the medial amygdala (MeA) and lateral septum (LS) on social discrimination abilities were dependent on the biological relevance of the social stimulus, thus comparing male juvenile versus adult female conspecifics. OXT release was increased in the LS of male rats during the retrieval, but not during the acquisition or maintenance, of social memory for male juvenile stimuli. Blockade of OXT activity by intracerebroventricular (ICV) administration of a specific OXT receptor antagonist (OXTR-A, rats: 0.75 µg/5 µl, mice: 2 µg/2 µl) immediately after acquisition of social memory impaired the maintenance of social memory, and consequently discrimination abilities during retrieval of social memory. In contrast, ICV OXTR-A was without effect when administered 20 min prior to retrieval of social memory in both species. Non-social memory measured in the object discrimination test was not affected by ICV OXTR-A in male mice, indicating that brain OXT is mainly required for memory formation in a social context. The biological relevance of the social stimulus seems to importantly determine social memory abilities, as male rats recognized a previously encountered female adult stimulus for at least 2h (versus 60 min for male juveniles), with a region-dependent contribution of endogenous OXT; while bilateral administration of OXTR-A into the MeA (0.1 µg/1 µl) impaired social memory for adult females only, administration of OXTR-A into the LS via retrodialysis (10 µg/ml, 1.0 µl/min) impaired social memory for both male juveniles and female adults. Overall, these results indicate that brain OXT is a critical mediator of social memory in male rodents and that, depending on the biological relevance of the social stimulus, distinct brain regions are recruited to mediate its effects.

Oxytocin-like receptors mediate pair bonding in a socially monogamous songbird.

Although many species form socially monogamous pair bonds, relevant neural mechanisms have been described for only a single species, the prairie vole (Microtus ochrogaster). In this species, pair bonding is strongly dependent upon the nonapeptides oxytocin (OT) and vasopressin, in females and males, respectively. Because monogamy has evolved many times in multiple lineages, data from additional species are required to determine whether similar peptide mechanisms modulate bonding when monogamy evolves independently. Here we test the hypothesis that OT-like receptor activation is required for pair bond formation in the socially monogamous zebra finch (Taeniopygia guttata). Males and females were administered chronic intracerebroventricular infusions of saline or an OT receptor antagonist and were observed twice daily for 3 days in a colony environment. A variety of affiliative, aggressive and other behaviours were quantified. The antagonist produced significant and selective effects on pair bonding (latency to pair; number of sessions paired; stable pairing) and the associated behaviour of allopreening. Importantly, findings for males follow the trends of females; this yields main effects of treatment in two-way ANOVAs, although within-sex analyses are significant only for females. These data provide evidence for both convergent evolution and species diversity in the neuroendocrine mechanisms of pair bonding.

Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish.

RATIONALE: Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders. OBJECTIVES: This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists. METHODS: Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH(2)-d(CH(2))(5)-[D-Tyr(2),Thr(4)]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist. RESULTS: All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415. CONCLUSIONS: For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.

Yes, I am ready now: differential effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats.

Sexual activity and partner intimacy results in several positive consequences in the context of stress-coping, both in males and females, such as reduced state anxiety in male rats after successful mating. However, in female rats, mating is a rewarding experience only when the estrous female is able to control sexual interactions, i.e., under paced-mating conditions. Here, we demonstrate that sex-steroid priming required for female mating is anxiolytic; subsequent sexual activity under paced mating conditions did not disrupt this anxiolytic priming effect, whereas mating under unpaced conditions increased anxiety-related behavior. In primed females, the release of the neuropeptide oxytocin (OT) within the hypothalamic paraventricular nucleus was found to be elevated and to further increase during paced, but not unpaced mating. Central administration of an OT receptor antagonist partly prevented priming/mating-induced anxiolysis indicating the involvement of brain OT in the anxiolysis triggered by priming and/or sexual activity.These findings reveal that the positive consequences of mating in females are dependent on her ability to control sexual interactions, and that brain OT release is at least in part the underlying neurobiological correlate.

Oxytocin in the periaqueductal grey regulates nociception in the rat.

Studies have demonstrated that oxytocin (OXT) plays important roles in pain modulation in the central nervous system, and there are OXT receptors in the periaqueductal grey (PAG). The experiment was designed to investigate the effect of OXT in the PAG on antinociception. The results showed that (1) intra-PAG injection of OXT increased the pain threshold, whereas the local administration of the high specific OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold in a dose-dependent manner; (2) Pain stimulation could elevate OXT concentration in the PAG perfusion liquid. The data suggested that OXT in the PAG was involved in the antinociceptive process through the OXT receptor.

Role of spinal V1a receptors in regulation of arterial pressure during acute and chronic osmotic stress.

Vasopressinergic neurons in the paraventricular nucleus project to areas in the spinal cord from which sympathetic nerves originate. This pathway is hypothesized to be involved in the regulation of mean arterial pressure (MAP), particularly under various conditions of osmotic stress. Several studies measuring sympathetic nerve activity support this hypothesis. However, the evidence that spinal vasopressin influences MAP under physiological or pathophysiological conditions in conscious animals is limited. The purpose of this study was to investigate, in conscious rats, if the increases in MAP during acute or chronic osmotic stimuli are due to activation of spinal vasopressin (V1a) receptors. Three conditions of osmotic stress were examined: acute intravenous hypertonic saline, 24- and 48-h water deprivation, and 4 wk of DOCA-salt treatment. Rats were chronically instrumented with an indwelling catheter for intrathecal injections and a radiotelemeter to measure MAP. In normotensive rats, intrathecal vasopressin and V1a agonist increased MAP, heart rate, and motor activity; these responses were blocked by pretreatment with an intrathecal V1a receptor antagonist. However, when the intrathecal V1a antagonist was given during the three conditions of osmotic stress to investigate the role of "endogenous" vasopressin, the antagonist had no effect on MAP, heart rate, or motor activity. Contrary to the hypothesis suggested by previous studies, these findings indicate that spinal V1a receptors are not required for elevations of MAP under conditions of acute or chronic osmotic stress in conscious rats.

Selective blockade of oxytocin and vasopressin V(1a) receptors in anaesthetised rats: evidence that activation of oxytocin receptors rather than V(1a) receptors increases sodium excretion.

BACKGROUND: Although it is known that moderate-to-high doses of the neurohypophysial hormones oxytocin and vasopressin are natriuretic, doubts remain over the identity of the receptors responsible. To address this issue, we have used highly selective antagonists of oxytocin and vasopressin receptors in animals with elevated endogenous circulating levels of the 2 hormones. METHODS: Rats were anaesthetised and prepared surgically for clearance studies, thereby raising plasma oxytocin and vasopressin concentrations. Sodium excretion, glomerular filtration rate and lithium clearance (an index of end-proximal fluid delivery) were measured: first during a control period, then after administration of the selective oxytocin receptor antagonist desGly-NH(2),d(CH(2))(5)[D-Trp(2),Thr(4),Dap(5)]OVT, the selective vasopressin V(1a) receptor antagonist d(CH(2))(5)[Tyr(Me)(2),Dab(5)]AVP, or vehicle alone. RESULTS: Absolute and fractional sodium excretion fell in rats given the oxytocin antagonist (by 32 and 27%, respectively, compared with corresponding values in vehicle-infused rats), but not in those given the V(1a) antagonist or vehicle. Antinatriuresis was associated with a small reduction in the ratio of sodium clearance to lithium clearance (an index of the fraction of distally delivered sodium that escapes reabsorption in the distal nephron). CONCLUSIONS: These results corroborate previous studies showing that activation of oxytocin receptors increases sodium excretion and imply that the natriuretic effect of elevated plasma vasopressin concentrations results from stimulation of oxytocin receptors.

Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse.

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) contribute to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Here, we characterized the phenotype of oxytocin receptor (OTR) and vasopressin-1A receptor (V1AR) null mutant mice in a battery of pain assays. Surprisingly, OTR knock-out mice displayed a pain phenotype identical to their wild-type littermates. Moreover, systemic administration of OXT dose-dependently produced analgesia in both wild-type and OTR knock-out mice in three different assays, the radiant-heat paw withdrawal test, the von Frey test of mechanical sensitivity, and the formalin test of inflammatory nociception. In contrast, OXT-induced analgesia was completely absent in V1AR knock-out mice. In wild-type mice, OXT-induced analgesia could be fully prevented by pretreatment with a V1AR but not an OTR antagonist. Receptor binding studies demonstrated that the distribution of OXT and AVP binding sites in mouse lumbar spinal cord resembles the pattern observed in rat. AVP binding sites diffusely label the lumbar spinal cord, whereas OXT binding sites cluster in the substantia gelatinosa of the dorsal horn. In contrast, quantitative real-time reverse transcription (RT)-PCR revealed that V1AR but not OTR mRNA is abundantly expressed in mouse dorsal root ganglia, where it localizes to small- and medium-diameter cells as shown by single-cell RT-PCR. Hence, V1ARs expressed in dorsal root ganglia might represent a previously unrecognized target for the analgesic action of OXT and AVP.