The role of oxytocin,vasopressin, and their receptors at nociceptors in peripheral pain modulation

Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.     

Dose-response relationships in attenuation of puromycin-induced amnesia by neurohypophyseal peptides

Intracerebral injections of puromycin one day after training of mice in a Y-maze cause amnesia when the animals are tested 7 days later. This amnesia was shown to be attenuated by various neurohypophyseal hormones, analogs and fragments, administered subcutaneously immediately after training. Dose-response relationships have been obtained for the attenuation of puromycin-induced amnesia in mice by selected neurohypophyseal peptides. All of the compounds tested reduce the amnesia in a dose-related way, suggesting that these peptides may interact with specific receptors to induce their central effect. Among the peptides studied the two most potent--i.e., those that cause substantial retention of memory at the lowest doses--are the neurohypophyseal hormone arginine vasopressin and Z-prolyl-leucyl-glycinamide (Z-MIF).     

The neuroendocrine basis of social recognition

All social relationships are dependent on an organism's ability to remember conspecifics. Social memory may be a unique form of memory, critical for reproduction, territorial defense, and the establishment of dominance hierarchies in a natural context. In the laboratory, social memory can be assessed reliably by measuring the reduction in investigation of a familiar partner relative to novel conspecifics. The neurohypophyseal neuropeptides oxytocin and vasopressin have been shown to influence a number of forms of social behavior, including affiliation, aggression, and reproduction. This article reviews vasopressin and oxytocin effects on social cognition, particularly the acquisition and retention of social recognition in rats and mice. Studies in rats have demonstrated that vasopressin in specific neural pathways, such as the lateral septum, is necessary for social recognition. As vasopressin facilitates recall when given after an initial encounter, the peptide appears important for the consolidation not the acquisition of a social memory. Although oxytocin has complex effects on social memory in rats, mice with a null mutation of the oxytocin gene are completely socially amnestic without other cognitive deficits evident. As oxytocin given centrally before but not after the initial encounter restores social recognition in these mutant mice, the neuropeptide appears critical for the acquisition rather than the consolidation phase of memory. Oxytocin's effects on social memory are mediated via a discrete cell population in the medial amygdala. These findings support the hypothesis that vasopressin and oxytocin are essential for social memory, although they appear to influence different cognitive processes and may modulate different neural systems. (c) Elsevier Science.     

Central Nervous System Effects of the Neurohypophyseal Hormones and Related Peptides

Summary: This review of the CNS effects of the neurohypophyseal hormones and related neuropeptides discusses recent data illustrating the significance of these principles in brain function, synthesis, distribution, in particular in extrahypothalamic brain structures, binding sites, and signal transduction. Binding sites for vasopressin of the vascular V_1a type have been found in the CNS and there is evidence for the existence of a subtype of the antidiuretic V₂ receptor in the brain. Also two types of oxytocin binding sites have been detected. One widely distributed throughout the CNS is comparable to the uterine type receptor and a sexually dimorphic slightly different type is found in the ventromedial nucleus. Vasopressin and oxytocin can be converted to highly selective C-terminal fragments as AVP-(4-9) and OXT-(4-9) and shorter fragments. Conversely they can be acetylated. This almost completely blocks intrinsic activity in bioassays for central and peripheral effects. Such modifications are a good example of the plasticity of a neuropeptide system. For a number of CNS effects of the neurohypophyseal hormones, the whole molecule is required, as it is for their endocrine effects. This is the case for the influence of vasopressin on social communication, temperature regulation, epilepsy, and barrel rotation which may be an animal model of febrile convulsions, and some aspects of the central regulation of the cardiovascular system and for oxytocin on sexual behavior, social communication, and grooming. Nonendocrine C-terminal conversion products seem to exert their effects exclusively on the brain. These neuropeptides modulate learning and memory processes, social recognition, and rewarded behavior. The neuroendocrine and neuropeptide effect of vasopressin and oxytocin and related neuropeptides often exert their CNS effects in an opposite way. Neurochemical and electrophysiological studies suggest that norepinephrine, dopamine, serotonin, and glutamate are the neurotransmitters involved in the influence of the neurohypophyseal hormones and related neuropeptides on brain function. It appears that adequate amounts of vasopressin and oxytocin to induce these effects are released at the appropriate sites of action. It is postulated that the mix of neuropeptides released in the brain in response to environmental changes qualifies the behavioral, neuroendocrine, and immune response and the response of the autonomic nervous and vegetative systems of the organism. Although various other neuropeptides, such as those colocalized in vasopressinergic and oxytocinergic neurons, those produced in pro-opiomelanocortin (POMC) systems, and others, play a role in the modulation of adaptive responses, the neurohypophyseal hormones are unique in that their production sites in the hypothalamus serve the periphery, the pituitary, and the brain.     

Neurohypophyseal peptides in the developing rat fetus

The quantitative changes in the content of the neurohypophyseal peptides, neurophysins, oxytocin, and vasopressin, were determined in the developing rat fetus. No neurohypophyseal peptides were found in 12-day fetuses. Neurophysins were first detected at day 13 and increased dramatically on day 14. The hormones vasopressin and oxytocin were not detected at day 13 and were measured at low levels at day 14. A 350-fold molar excess of neurophysin to hormones existed at day 14. From day 14 to day 19 the total content of neurophysin decreased while the content of vasopressin and oxytocin slowly increased. At day 19 there was a near molar equivalency between the content of neurophysin and that of the neurohypophyseal hormones. From day 18 to day 22 there was a sharp increase in the content of vasopressin while the content of neurophysin and oxytocin increased less dramatically. At term there was a molar excess of vasopressin, and the molar ratio of neurophysin to hormone at the time of delivery was 0.12. Measurement of vasopressin by different radioimmunoassays and by bioassay indicated no contribution of arginine-vasotocin to the measured vasopressin.     

Arginine vasopressin induces the expression of c-fos in the mouse septum and hippocampus

Arginine vasopressin is a neuropeptide that has been shown to modulate functional ethanol tolerance and memory processes. These actions of vasopressin in the CNS have been shown by us and others to be mediated by V1 receptors. Intracerebroventricular injection of vasopressin in mice resulted in a substantial increase in mRNA for the proto-oncogene c-fos in septum and hippocampus, but no increase in cerebral cortex. A V1-selective agonist also increased septal c-fos mRNA levels, while a V2-selective agonist was less effective. Similarly, the response to vasopressin was more effectively blocked by a V1- than a V2-selective antagonist. These results indicate that vasopressin acts specifically at V1 receptors in mouse septum and hippocampus to increase c-fos mRNA. The vasopressin metabolite, AVP(4-9), also increased c-fos mRNA levels in septum and hippocampus, while the response to oxytocin, which has different effects from vasopressin on memory and tolerance, was greater in hippocampus than in septum. Nerve growth factor, in contrast to the other peptides, had a more pronounced effect on c-fos mRNA levels in cerebral cortex than in the other brain areas. Increased c-fos expression has been hypothesized to play a role in neuroadaptation, and these results suggest that modulation of septal c-fos expression could be important for vasopressin effects on ethanol tolerance and/or memory.     

Neurohypophyseal peptides as regulators of growth and development

In addition to their classical hormonal role, the neurohypophyseal peptides vasopressin (AVP) and oxytocin (OT) are also implicated as regulators of growth and development. Mitogenic actions of AVP are particularly well characterized and may underly the potential role of AVP as an autocrine regulator of tumor growth. Effects of AVP and OT on neural development are suggested by numerous studies, but definitive physiological evidence is lacking. Current studies on the molecular characterization of AVP and OT receptors, and on transgenic animals will provide insights into the developmental actions of neurohypophyseal peptides.     

Sites of behavioral and neurochemical action of ACTH-like peptides and neurohypophyseal hormones

In order to localize the site of action of neuropeptides in relation to their effects on behavior and memory various approaches have been used. As a result of studies using rats bearing lesions in different areas of the limbic system as well as of studies in which neuropeptides were locally applied into various areas of the brain it appeared that the limbic system (amygdala, hippocampus, septum and some thalamic areas) plays an essential role in the effect of vasopressin and ACTH and their derivatives on behavior and memory. Neurochemical studies generally indicate that changes occur in catecholamine utilization in these various limbic regions upon administration of these neuropeptides. It can be concluded that the effects of vasopressin in the terminal regions of the coeruleo-telencephalic noradrenalin system correlate with its effects on consolidation of memory. It is likely that the effects of vasopressin on other transmitter systems (e.g. dopamine in the amygdala and serotonin in the hippocampus) correspond with the effect of this neuropeptide on retrieval processes. In addition, regional differences in biotransformation of the neurohypophyseal hormones suggest that different patterns of behaviorally active fragments of these peptides may be present locally in the brain.     

Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF

The penetration of neurohypophyseal peptides after peripheral administration into the cerebrospinal fluid (CSF) was studied in freely moving rats. In addition, the clearance of these peptides from CSF was investigated. Increased concentrations of vasopressin (AVP) in CSF were detectable 2 min after s.c. injection of 5.0 micrograms of this peptide. Peak concentration was reached at 5 min after administration and this level declined slowly over the next hour. Administration of 5.0 micrograms oxytocin (OXT) s.c. or i.v. resulted in increased OXT levels in CSF within 10 min after application. After 60 min a significant elevation of OXT in CSF was no longer present. These data reveal that approximately 0.002% of the peripherally applied amount of AVP or OXT reached the central nervous system at 10 min after injection. AVP (2.5 ng) and OXT (5.0 ng) applied into one of the lateral brain ventricles reached the cisternal cavity within 2 min after administration. Both neuropeptides were cleared from the CSF with terminal half-times of 26 and 19 min for AVP and OXT, respectively. The present data demonstrate that neurohypophyseal hormones do cross the blood-brain barrier in amounts obviously sufficient to induce central actions.     

Nα-Acetyl-Vasopressin- and Nα-Acetyl-Oxytocin-Like Substances: Isolation and Characterization in the Rat Neurointermediate Pituitary and Presence in the Brain

Post-translational modifications of vasopressin and oxytocin in pituitary and brain were investigated in view of recent evidence that oxytocin is partly N^α-acetyfated in the bovine pineal gland. Two peptides were isolated from the neurointermediate lobe of the rat pituitary gland and characterized as N^α-acetyl-vasopressin and N^α-acetyl-oxytocin, based on chromatographic and immunological properties as well as the blocked N-terminus. In the neurointermediate pituitary the acetylated forms represented approximately 1% of the vasopressin and oxytocin contents. These two peptides were also detected in some, but not all, investigated brain areas. The highest degree of acetylation was found in the pineal gland. In all regions acetylation of oxytocin was more abundant than that of vasopressin. The data indicate that acetylation of vasopressin and oxytocin generally occurs as a post-translational modification. They support the concept that acetylation may represent a mechanism aimed to control bioactivity of the neurohypophyseal hormones.     

Vasopressin--oxytocin in cerebrospinal fluid of schizophrenic patients and normal controls

Vasopressin and oxytocin seem to be involved in the processes of learning and memory in animals and probably in man. These peptides appear to have opposite effects in that vasopressin improves memory processes and oxytocin produces amnestic effects. We measured these neuropeptides in the cerebrospinal fluid of schizophrenic patients with and without neuroleptic treatment, psychiatrically healthy controls and drug-free patients before and after three weeks' neuroleptic treatment. There were no significant differences in vasopressin concentrations between schizophrenics and controls. No influence of neuroleptic treatment on vasopressin concentrations was detected. In contrast, concentrations of oxytocin were increased in all schizophrenic patients and were higher in those receiving neuroleptic treatment. In addition, oxytocin concentrations increased after three weeks' neuroleptic treatment. Drug-induced increase of oxytocin concentrations may be of significance in the clinically observed amnestic syndromes and debilitation in schizophrenics treated with neuroleptics.     

Vasopressin peptide (DDAVP) may narrow the focus of attention in normal elderly

Administration of DDAVP (1 desamino-8-D-arginine vasopressin), a form of vasopressin with little pressor action, has been shown to improve cognitive performance in the elderly. It remains unclear whether memory processes are specifically influenced or more general processes are altered. Fifteen elderly subjects performed a central mental arithmetic task and a peripheral choice reaction time task in DDAVP and control conditions. DDAVP slowed reaction times to peripheral lights but did not alter arithmetic performance. The results suggest that DDAVP increases the proportion of attention allocated to primary task performance by decreasing attention to secondary tasks. This shift does not appear to be mediated by any action of DDAVP on peripheral cardiovascular function.     

Neuropeptides related to neurohypophyseal hormones interfere with apomorphine-induced behavioral changes

The interaction between peptides related to neurohypophyseal hormones and brain dopaminergic systems was studied by investigating in rats the effect of these peptides on behavioral changes induced by graded doses of the specific dopamine agonist apomorphine. Low doses of this drug induce hypoactivity of the animals, while higher doses result in hyperactivity and stereotyped sniffing. Desglycinamide ⁹[Arg⁸] vasopressin (DG-AVP), prolyl-leucyl-glycinamide (PLG) and oxytocin did not interfere with the behavioral responses induced by the higher doses of apomorphine. Peptide treatment made the rats more sensitive to apomorphine with respect to the drug induced hypoactivity. PLG and especially DG-AVP were more effective than oxytocin. It is concluded that these peptides may have a selective action on distinct dopaminergic receptor systems in the brain, that are presumably located presynaptically in the nucleus accumbens area.     

Comparison of the distribution of oxytocin and vasopressin in the rat brain

While immunohistochemistry has been used extensively to map both oxytocin (OT) and vasopressin (VP) pathways in the brain, little information is available concerning the quantitative distribution of these hormones--particularly oxytocin. We have isolated oxytocin from extrahypothalamic regions of the rat brain and shown it to behave identically with standard oxytocin in radioimmunoassay (RIA) and on high-performance liquid chromatography. Using sensitive RIA we have measured and compared levels of both oxytocin and vasopressin in the rat brain. Both hormones are widely distributed, with the largest amounts outside the hypothalamus being found in the locus coeruleus. Considerable quantities of both peptides (but particularly oxytocin) are found in mesencephalic, pontine and medullary nuclei. This distribution is similar to that of the catecholamines, and the possible interaction of oxytocin and vasopressin with catecholaminergic pathways in the central control of various functions is discussed.     

Differential role of specific cardiovascular neuropeptides in pain regulation: Relevance to cardiovascular diseases

In many instances, the perception of pain is disproportionate to the strength of the algesic stimulus. Excessive or inadequate pain sensation is frequently observed in cardiovascular diseases, especially in coronary ischemia. The mechanisms responsible for individual differences in the perception of cardiovascular pain are not well recognized. Cardiovascular disorders may provoke pain in multiple ways engaging molecules released locally in the heart due to tissue ischemia, inflammation or cellular stress, and through neurogenic and endocrine mechanisms brought into action by hemodynamic disturbances. Cardiovascular neuropeptides, namely angiotensin II (Ang II), angiotensin-(1-7) [Ang-(1-7)], vasopressin, oxytocin, and orexins belong to this group. Although participation of these peptides in the regulation of circulation and pain has been firmly established, their mutual interaction in the regulation of pain in cardiovascular diseases has not been profoundly analyzed. In the present review we discuss the regulation of the release, and mechanisms of the central and systemic actions of these peptides on the cardiovascular system in the context of their central and peripheral nociceptive (Ang II) and antinociceptive [Ang-(1-7), vasopressin, oxytocin, orexins] properties. We also consider the possibility that they may play a significant role in the modulation of pain in cardiovascular diseases. The rationale for focusing attention on these very compounds was based on the following premises (1) cardiovascular disturbances influence the release of these peptides (2) they regulate vascular tone and cardiac function and can influence the intensity of ischemia – the factor initiating pain signals in the cardiovascular system, (3) they differentially modulate nociception through peripheral and central mechanisms, and their effect strongly depends on specific receptors and site of action. Accordingly, an altered release of these peptides and/or pharmacological blockade of their receptors may have a significant but different impact on individual sensation of pain and comfort of an individual patient.     

Differential release of vasopressin and oxytocin in response to abdominal vagal afferent stimulation or apomorphine in the ferret

The aim of this study was to investigate whether direct afferent stimulation of the abdominal vagus promote release of the neurohypophyseal hormones. The nucleus of the solitary tract is the major recipient of vagal afferent information, and this region of the brainstem may also be activated by stimulation of the area postrema. For this reason apomorphine, a D₂ dopaminergic agonist which acts on the area postrema, and can evoke vasopressin secretion in man, was also investigated for its effect on vasopressin and oxytocin release. Our results show that vasopressin, but not oxytocin is released in vast amounts in response to electrical afferent stimulation of the abdominal vagus. Administration of apomorphine also evoked a massive vasopressin release with less marked effects on oxytocin. The possible functional implications of these results are discussed especially in the context of nausea and vomiting.     

Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior.

We investigated the influence of C-terminal fragments of oxytocin (OT) and arginine vasopressin (AVP) on conditioned freezing behavior. Subcutaneous injections of 0.3 microgram AVP(4-9) or OT(4-9) given to rats after shock training or before behavioral observation significantly altered fear-induced freezing behavior. Animals treated with OT hexapeptide froze less than controls, while animals treated with AVP hexapeptide froze more. These results support the concept that the hexapeptide metabolites of oxytocin and vasopressin can selectively modulate certain behavioral processes, and that these peptides have opposite effects on performance in behavioral tests designed to evaluate memory consolidation and retrieval.     

A functional role for opioid peptides in the differential secretion of vasopressin and oxytocin

The presence of opioid peptides and opiate receptors in the hypothalamo-neurohypophysial system, as well as the inhibitory effects of enkephalins and beta-endorphin on release of oxytocin and vasopressin have been well documented. The physiological importance of opioid peptides in this classical neurosecretory system, however, has remained illusive. In the present study we tested the effects of naltrexone on the plasma concentrations of oxytocin and vasopressin during dehydration, hemorrhage and suckling in the conscious rat. We obtained evidence supporting the hypothesis that opioid peptides inhibit oxytocin release and thereby promote the preferential secretion of vasopressin when it is of functional importance to maintain homeostasis during dehydration and hemorrhage. Our data support the concept that the coexistence of a neuromodulator and a neurohormone in the same neuron, as demonstrated for vasopressin with dynorphin or leucine-enkephalin, serves to regulate the differential release of two biologically different, yet evolutionarily-related, neurohormones, e.g. oxytocin and vasopressin, from the same neuroendocrine system.     

Intranasal Application of Vasopressin Fails to Elicit Changes in Brain Immediate Early Gene Expression,Neural Activity and Behavioural Performance of Rats

Intranasal administration has been widely used to investigate the effects of the neuropeptides vasopressin and oxytocin on human behaviour and neurological disorders, although exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. In the present study, we investigated whether the intranasal administration of vasopressin and oxytocin to rats induces the expression of the immediate-early gene product Fos in brain areas that are sensitive to centrally-administered peptide, whether it alters neuronal activity in the way that centrally-administered peptide does, and whether it affects behaviour in the ways that are expected from studies of centrally-administered peptide. We found that, whereas i.c.v. injection of very low doses of vasopressin or oxytocin increased Fos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. By contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short-term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data obtained in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behaviour in the ways described for central administration of the peptides.     

Vasopressin and related peptides: Animal and human studies

In animals, vasopressin and related peptides are present in specific neuronal pathways in the brain and modulate brain processes. It has been suggested that in particular memory processes, including consolidation and retrieval, short and long term memories are facilitated by vasopressin. Evidence has been presented that endogenous vasopressin is involved in these processes. But also other effects of these peptides e.g. an attenuation of acquisition of heroin self-administration have been reported. Vasopressin and related peptides have been administered to humans in a number of studies including volunteers and various patient populations with and without complaints about memory. Beneficial effects on several aspects of memory, learning, attention and concentration have been found, but not in all studies. Patients with severe deficits seem to benefit less from the peptide treatment. This may be related to the amount of brain damage. Beneficial effects of vasopressin treatment have been reported in schizophrenics and heroin addicts. In addition effects on social behavior, energy and mood of certain patients have been noted. The target patient population for vasopressin neuropeptide is thus not yet well defined. With respect to cognitive disorders, sophisticated neuropsychological test procedures, including information-processing tasks, may contribute to define such a patient population. These tasks may also be applied for treatment evaluation. It should however be kept in mind that other interesting influences of vasopressin e.g. on social behavior, mood and addictive behavior, may also appear of clinical significance. Future studies in humans may yield more detailed information in this respect. Desglycinamide (Arg⁸)-vasopressin or the recently discovered potent fragments of vasopressin may be recommended for these studies, because these peptides are practically devoid of the peripheral “side” effects on water homeostasis and blood pressure accompanying treatment with vasopressin or desamino-(D-Arg⁸)vasopressin (DDAVP).