Oxytocin actions

Condes-Lara M, Maie lA, EHckenson AH (2005) Oxytocin actions on afferent evoked spinal cord neuronal activities in neuropathic but not in normal rats. Brain Res 1045 124—133 Conn PJ, Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu... 

Carboprost (prostaglandin F a analogue) is used for postpartum haemorrhage (resistant to ergometiine and oxytocin) for its oxytocin action. It is highly effective. Adverse effects include hypertension, asthma and pulmonary oedema. 

Oxytocin and Vasopressin Receptors. The actions of oxytocin and vasopressin are mediated through their interactions with receptors. Different receptor types as well as different second messenger responses help explain their diverse activities in spite of the hormones stmctural similarities. Thus oxytocin has at least one separate receptor and vasopressin has been shown to have two principal receptor types, and V2. Subclasses of these receptors have been demonstrated, and species differences further compHcate experimental analysis. It is apparent that both oxytocin and receptors function through the GP/1 phosphoHpase C complex (75), while the V2 receptors activate cycHc AMP (76). 

Vasopressin is closely related to oxytocin and both peptides are cyclic in that they contain a disulphide bridge. Although much is known about the peripheral actions of the peptides the extent of our current knowledge of their possible CNS function is that vasopressin appears to act as a cognitive enhancer and has positive effects on learning processes in animals. Vasopressin acts on three receptors, Via and b and a V2 receptor. 

Ki of 6 nM against a guinea-pig uterine oxytocin preparation and at least 100-fold selectivity over rat vasopressin tissue preparations. These molecules show a pseudo-irreversible pharmacology, with an extended action against spontaneous contractibility of rat uterus 24 h post partum. 

The posterior pituitary is innervated by direct nervous stimulation from the hypothalamus, resulting in the release of specific hormones. The hypothalamus synthesizes two hormones, oxytocin and vasopressin. These hormones are stored in and released from the posterior pituitary lobe. Oxytocin exerts two actions (1) it promotes uterine contractions during labor, and (2) it contracts the smooth muscles in the breast to stimulate the release of milk from the mammary gland during lactation. Vasopressin is an antidiuretic hormone (ADH) essential for proper fluid and electrolyte balance in the body. Specifically, vasopressin increases the permeability of the distal convoluted tubules and collecting ducts of the nephrons to water. This causes the kidney to excrete less water in the urine. Consequently, the urine becomes more concentrated as water is conserved. 

As its name implies, the neurohypophysis is derived embryonically from nervous tissue. It is essentially an outgrowth of the hypothalamus and is composed of bundles of axons, or neural tracts, of neurosecretory cells originating in two hypothalamic nuclei. These neurons are referred to as neurosecretory cells because they generate action potentials as well as synthesize hormones. The cell bodies of the neurosecretory cells in the supraoptic nuclei produce primarily antidiuretic hormone (ADH) and the cell bodies of the paraventricular nuclei produce primarily oxytocin. These hormones are then transported down the axons to the neurohypophysis and stored in membrane-bound vesicles in the neuron terminals. Much like neurotransmitters, the hormones are released in response to the arrival of action potentials at the neuron terminal. 

As discussed previously, the neurohypophysis has a direct anatomical connection to the hypothalamus. Therefore, the hypothalamus regulates the release of hormones from the neurohypophysis by way of neuronal signals. Action potentials generated by the neurosecretory cells originating in the hypothalamus are transmitted down the neuronal axons to the nerve terminals in the neurohypophysis and stimulate the release of the hormones into the blood. The tracts formed by these axons are referred to as hypothalamic-hypophyseal tracts (see Figure 10.2). The action potentials are initiated by various forms of sensory input to the hypothalamus. Specific forms of sensory input that regulate the release of ADH and oxytocin are described in subsequent sections in this chapter. 

Progesterone produces direct membrane effects [16]. These include actions that promote maturation of spermatozoa as well as oocytes and facilitation of the release of neurotransmitters such as dopamine and LH-releasing hormone (LHRH) (Fig. 52-7). Membrane actions of progesterone also activate oxytocin receptors in the hypothalamus in a way that enables oxytocin to turn on sexual behavior in the estrogen-primed female rat [3],... 

None of these findings undermines the importance of the intracellular genomic actions of steroids. Rather, they increase the richness of the cellular actions of steroid hormones and raise the possibility that there may be connections between genomic and nongenomic actions of steroids. For example, genomic action may induce receptors that mediate nongenomic effects. Moreover, the activation of oxytocin receptors by progesterone is dependent... 

In order to review these putative relationships it is first useful to define a subset of well-characterized hormones and neurotransmitters that have been implicated in behavior. The chemicals selected for discussion here are among those for which a robust relationship with behavior has been proposed, including steroids (estrogens, progestins, androgens and glucocorticoids), proteins (prolactin) and the neuropeptides (oxytocin and vasopressin). All of these chemicals may act as hormones, neurotransmitters and/or neuromodulators. In addition, to understand the action of these hormones, it is helpful to be familiar with some of the more common neurotransmitters (described below). Space does not permit a discussion of the behavioral effects of many additional compounds with endocrine or paracrine properties. 

Historically vasopressin and oxytocin, two nonapep-tides, were the first peptide neurohormones to be considered they are stored in the neurohypophysis and released into the bloodstream upon an appropriate stimulus. In the periphery, oxytocin stimulates the contraction of epididymal and uterine smooth muscle (see Chapter 62) and vasopressin (antidiuretic hormone) facilitates the reabsorption of water from the kidney tubules. In addition to these well-accepted roles as neurohormones, there is convincing evidence that these compounds function as neurotransmitters they both possess potent inhibitory actions on neurohypophyseal neurons. The significance of their neurotransmitter function is not yet clear. 

Oxytocin (Pitocin, Syntocinon) is a cyclic 8-amino acid peptide that is synthesized in the paraventricular nucleus of the hypothalamus and transported within hypothalamic neurons (in association with neurophysin) to the posterior pituitary for storage. Its mechanism of action involves the direct stimulation of oxytocin receptors found on the myometrial cells. Oxytocin circulates unbound in the plasma, where it has a half-Ufe of approximately 15 minutes. It is primarily inactivated in the kidneys and liver. 

Oxytocin, a nine amino acid peptide, is synthesized primarily in the paraventricular and supraoptic (SON) nuclei of the hypothalamus, from which it is released to the general circulation through the posterior pituitary (Insel et ah, 1997). However, oxytocinergic fibers have also been found to project from the PVN to the limbic system and several autonomic centers in the brain stem. This central OT pool appears to be independent of pituitary OT release cerebrospinal fluid (CSF) and plasma OT responses to numerous stimuli are not correlated (Insel, 1997). Oxytocin and its analog (or partner) peptide vasopressin are found only in mammals. A related peptide, vasotocin, thought to be the evolutionary precedent of these peptides, is found in reptiles and birds. The first known actions of OT were its peripheral effects on the physiology of new mothers. In mammals, OT stimulates milk ejection and uterine contraction, essential aspects of maternal physiology (Insel et ah, 1997). 

McCarthy, M.M. and Altemus M. (1997) Central nervous system actions of oxytocin and modulation of behavior in humans. Mol Med Today 3 269-275. 

Den Boer JA, Westenberg HGM No evidence for anticompulsive action of oxytocin. Chn Neuropharmacol 15[1) 307B, 1992a... 

Oxytocin (OT) is a nonapeptide in which six amino acids form a ring closed by a disulfide bridge, while the ring itself forms an antiparallel pleated sheet. The tail portion of the peptide, composed of Pro-Leu-Gly-NHj, is also rigidly held in a folded conformation. Oxytocin causes the powerful contraction of some smooth muscles and plays a vital role in milk ejection (not to be confused with milk secretion, which is regulated by prolactin). It also has uterotonic action, contracting the muscles of the uterus, and is therefore used clinically to induce childbirth. 

Vasopressin occurs in two variations arginine-vasopressin (AVP) and lysine-vasopressin (LVP), in which Arg is replaced by Lys. The conformation of these hormones is almost identical to that of oxytocin, except that the terminal tail is con-formationally free and not held by the ring. The physiological role of the vasopressins is the regulation of water reabsorption in the renal tubules (i.e., an antidiuretic action). In high doses, they promote the contraction of arterioles and capillaries and an increase in blood pressure hence the name of these hormones. Because of their very similar structures, OT and VP overlap in a number of effects. 

Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction. 

The action of HA is indirect, mediated primarily via activation of corticotropin-releasing hormone (CRH) originating in parvocellular neurons in the PVN and secondly via vasopressin (AVP) originating in parvo- and magnocellular neurons in the PVN and in the SON [18-24]. The effect of CRH is predominantly mediating in character (i.e. HA releases CRH which subsequently stimulates ACTH secretion) [18] while the effect of AVP seem to be mediating as well as permissive in character (i.e. AVP has to be present in order for HA to exert its effect on ACTH secretion) [25]. Besides these two important mediators, prostaglandins are involved in HA-induced release of the POMC-derived peptides from the anterior lobe [26], whereas catecholamines, oxytocin (OT) and serotonin (5-HT) do not participate [27-28, Willems et al. (unpublished observations)]. 

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