Use of copeptin in interpretation of the water deprivation test.

INTRODUCTION: Currently, the water deprivation test remains the standard method for distinguishing primary polydipsia (PP) from cranial diabetes insipidus (cDI) and nephrogenic diabetes insipidus (nDI). There is increasing interest in a direct estimate of antidiuretic hormone using plasma copeptin as a stable and reliable surrogate marker. We present our experience of measuring copeptin during the water deprivation test. METHODS: Forty-seven people (17 men) underwent a standard water deprivation test between 2013 and 2021. Plasma copeptin was measured at the start of the test and at the end of the period of water deprivation (maximum osmotic stimulation). Results were classified using prespecified diagnostic criteria. As it is known that a significant proportion of tests will reveal indeterminate results, a final diagnosis was obtained by including relevant pre- and post-test clinical criteria. This diagnosis was then used to plan individual treatment. RESULTS: Basal and stimulated copeptin were significantly higher in the nephrogenic DI group than other categories (p < .001). There was no significant difference in basal or stimulated copeptin between PP, cDI or partial DI. Nine results were indeterminate where the serum and urine osmolality did not give a unified diagnosis. Stimulated copeptin was helpful in reclassifying these patients into the final diagnostic groups. CONCLUSION: Plasma copeptin has additional clinical utility in interpretation of the water deprivation test and may continue to have a place alongside newer stimulation tests.

Resilience to drought in semi-desert sheep: Effects of water restriction during pregnancy on placental efficiency in the Awassi breed.

Assessing the resilience of Awassi sheep to water shortages during pregnancy, thereby investigating the effects of water scarcity on gestation efficiency in animals, could provide valuable and pertinent insight into future scenarios posed by climate change risks. In this study, 40 pregnant Awassi ewes randomly allocated to free watering group (C, n = 20) received water ad libitum and the water restricted group (WR) received 50% less water than the amount provided to group C. Water restriction decreased (p < .05) lambs' birth weights, placental weights (PWs), and cotyledon numbers (CNs). Placental efficiency (PE) and cotyledon efficiency (CE) were significantly higher in the WR group (p < .05). A marked difference in cotyledon weight - an increase of 12.1% - was recorded in the C group. The body weights of the pregnant ewes in the WR group decreased significantly (p < .05) by 22% during pregnancy. Significant increases (p < .05) in plasma ADH, cholesterol, Cl- , and Na+ levels were observed in the WR group ewes, indicating intense dehydration. We conclude that the Awassi breed of sheep can endure 50% water restriction during pregnancy and maintain successful parturition, a key outcome for sustainability.

The effect of long-term dehydration and subsequent rehydration on markers of inflammation, oxidative stress and apoptosis in the camel kidney.

BACKGROUND: Dehydration has deleterious effects in many species, but camels tolerate long periods of water deprivation without serious health compromise. The kidney plays crucial role in water conservation, however, some reports point to elevated kidney function tests in dehydrated camels. In this work, we investigated the effects of dehydration and rehydration on kidney cortex and medulla with respect to pro-inflammatory markers, oxidative stress and apoptosis along with corresponding gene expression. RESULTS: The cytokines IL-1ß and IL-18 levels were significantly elevated in the kidney cortex of dehydrated camel, possibly expressed by tubular epithelium, podocytes and/or mesangial cells. Elevation of IL-18 persisted after rehydration. Dehydration induced oxidative stress in kidney cortex evident by significant increases in MDA and GSH, but significant decreases in SOD and CAT. In the medulla, CAT decreased significantly, but MDA, GSH and SOD levels were not affected. Rehydration abolished the oxidative stress. In parallel with the increased levels of MDA, we observed increased levels of PTGS1 mRNA, in MDA synthesis pathway. GCLC mRNA expression level, involved in GSH synthesis, was upregulated in kidney cortex by rehydration. However, both SOD1 and SOD3 mRNA levels dropped, in parallel with SOD activity, in the cortex by dehydration. There were significant increases in caspases 3 and 9, p53 and PARP1, indicating apoptosis was triggered by intrinsic pathway. Expression of BCL2l1 mRNA levels, encoding for BCL-xL, was down regulated by dehydration in cortex. CASP3 expression level increased significantly in medulla by dehydration and continued after rehydration whereas TP53 expression increased in cortex by rehydration. Changes in caspase 8 and TNF-α were negligible to instigate extrinsic apoptotic trail. Generally, apoptotic markers were extremely variable after rehydration indicating that animals did not fully recover within three days. CONCLUSIONS: Dehydration causes oxidative stress in kidney cortex and apoptosis in cortex and medulla. Kidney cortex and medulla were not homogeneous in all parameters investigated indicating different response to dehydration/rehydration. Some changes in tested parameters directly correlate with alteration in steady-state mRNA levels.

Recovery of hematocrit and fat deposits varies by cage size in food-restricted captive red crossbills (Loxia curvirostra).

Hematocrit-or the percent volume of red blood cells in whole blood-is thought to fluctuate adaptively in response to changing oxygen demands that occur during different life activities and in different environments. Because red blood cells are made from materials that can be limiting, however, it is thought that hematocrit may also reflect general body condition and access to resources. We tested the effect of hydration state, resource restriction (i.e., time available to forage), and activity (i.e., different cage sizes) on hematocrit in captive red crossbills (Loxia curvirostra). We found no evidence that a mild dehydration protocol impacts hematocrit and only weak support that mild food restriction impacts hematocrit. Food restriction did, however, reduce fat deposits and fat loss was more significant in birds that were also sampled for hematocrit. Furthermore, food-restricted birds housed in flight aviaries recovered hematocrit but not fat stores following repeated blood sampling, whereas birds housed in small cages lost additional hematocrit but mitigated fat loss following successive bleeds. Together these results suggest that different flight demands may determine response to blood loss during food restriction, potentially revealing a trade-off between fat storage and red blood cell development. Our results also demonstrate the need for scientists to carefully record hematocrit data and the time course across which multiple tubes of blood are collected to avoid confounding real patterns with variation generated by sampling protocol.

Short-term water deprivation attenuates the exercise pressor reflex in older female adults.

Older adults have reduced fluid intake and impaired body fluid and electrolyte regulation. Older female adults exhibit exaggerated exercise blood pressure (BP) responses, which is associated with an increased risk of adverse cardiovascular events. However, it is unclear if dysregulated body fluid homeostasis contributes to altered exercise BP responses in older female adults. We tested the hypothesis that short-term water deprivation (WD) increases exercise BP responses in older female adults. Fifteen female adults (eight young [25 ± 6 years] and seven older [65 ± 6 years]) completed two experimental conditions in random crossover fashion; a euhydration control condition and a stepwise reduction in water intake over three days concluding with a 16-hr WD period. During both trials, beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) were continuously assessed during rest, handgrip exercise (30% MVC), and post-exercise ischemia (metaboreflex isolation). At screening, older compared to young female adults had greater systolic and diastolic BP (p ≤ .02). Accelerometer-assessed habitual physical activity was not different between groups (p = .65). Following WD, 24-hr urine flow rate decreased, whereas thirst, urine specific gravity, and plasma osmolality increased (condition: p < .05 for all), but these WD-induced changes were not different between age groups (interaction: p ≥ .31 for all). Resting systolic and diastolic BP values were higher in older compared to young adults (p < .01 for both), but were not different between experimental conditions (p ≥ .20). In contrast to our hypothesis, WD was associated with attenuated systolic BP responses during handgrip exercise (post hoc: p < .01) and post-exercise ischemia (post hoc: p = .03) in older, but not young, female adults. These data suggest that reduced water intake-induced challenges to body fluid homeostasis do not contribute to exaggerated exercise BP responses in post-menopausal female adults.

Fluid Restriction Therapy for Chronic SIAD; Results of a Prospective Randomized Controlled Trial.

CONTEXT: Fluid restriction (FR) is the recommended first-line treatment for syndrome of inappropriate antidiuresis (SIAD), despite the lack of prospective data to support its efficacy. DESIGN: A prospective nonblinded randomized controlled trial of FR versus no treatment in chronic SIAD. INTERVENTIONS AND OUTCOME: A total of 46 patients with chronic asymptomatic SIAD were randomized to either FR (1 liter/day) or no specific hyponatremia treatment (NoTx) for 1 month. The primary endpoints were change in plasma sodium concentration (pNa) at days 4 and 30. RESULTS: Median baseline pNa was similar in the 2 groups [127 mmol/L (interquartile range [IQR] 126-129) FR and 128 mmol/L (IQR 126-129) NoTx, P = 0.36]. PNa rose by 3 mmol/L (IQR 2-4) after 3 days FR, compared with 1 mmol/L (IQR 0-3) NoTx, P = 0.005. There was minimal additional rise in pNa by day 30; median pNa increased from baseline by 4 mmol/L (IQR 2-6) in FR, compared with 1 mmol/L (IQR 0-1) NoTx, P = 0.04. After 3 days, 17% of FR had a rise in pNa of ≥5 mmol/L, compared with 4% NoTx, RR 4.0 (95% CI 0.66-25.69), P = 0.35. After 3 days, 61% of FR corrected pNa to ≥130 mmol/L, compared with 39% of NoTx, RR 1.56 (95% CI 0.87-2.94), P = 0.24. CONCLUSION: FR induces a modest early rise in pNa in patients with chronic SIAD, with minimal additional rise thereafter, and it is well-tolerated. More than one-third of patients fail to reach a pNa ≥130 mmol/L after 3 days of FR, emphasizing the clinical need for additional therapies for SIAD in some patients.

A randomized controlled trial of restricted versus standard fluid management in late preterm and term infants with transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn(TTNB) is the most common respiratory morbidity in late preterm and term babies and is pathophysiologically related to delayed lung fluid clearance after birth. Mimicking low physiological fluid intake in the initial period of life may accelerate the recovery from TTNB. In a randomized controlled trial, we compared the roles of restricted versus standard fluid management in babies with TTNB requiring respiratory support. METHODS: This parallel group,non-blinded, stratified randomized controlled trial was conducted in a level III neonatal unit of eastern India. Late preterm and term babies with TTNB requiring continuous positive airway pressure (CPAP) were randomly allocated to standard and restricted fluid arms for the first 72 hours (hrs). Primary outcome was CPAP duration. RESULTS: In total, 100 babies were enrolled in this study with 50 babies in each arm. CPAP duration was significantly less in the restricted arm (48[42, 54] hrs vs 54[48,72] hrs, p = 0.002). However, no difference was observed in the incidence of CPAP failure between the two arms. In the subgroup analysis, the benefit of reduced CPAP duration persisted in late preterm but not in term infants. However, the effect was not significant in the late preterm babies exposed to antenatal steroid. CONCLUSION: This trial demonstrated the safety and effectiveness of restrictive fluid strategy in reducing CPAP duration in late preterm and term babies with TTNB. Late preterm babies, especially those not exposed to antenatal steroid were the most benefitted by this strategy.

Neurobehavioral and neurophysiological effects of prolonged osmotic stress in rats: A focus on anxiety state and pain perception.

This study examined the effect of prolonged water deprivation, in rat, on 5-HT and TH- immuno-expression in Dorsal Raphe Nucleus (DRN), Substantia Nigra pars compacta (SNc), Ventral Tegmental Area (VTA), and Magnus Raphe Nucleus (MRN). In parallel, we evaluated the anxiety state and pain perception in dehydrated rats. Our Findings revealed that dehydrated rats exhibited more preference for the dark compartment, suggesting that prolonged water deprivation is associated to an anxiogenic effect. After one week, 5 H T IR in the DRN of dehydrated rates showed a significant decrease. This was reversed to a significant increase post week 2 of dehydration. Our findings also demonstrated that TH-IR in DRN, MRN, SNc and VTA neuronal systems is significantly and gradually enhanced after 1-and-2-week osmotic stress. In addition, our results proved that all dehydrated rats were characterized by a significant and proportional rise of the reaction time to the nociceptive response in the hot plate test, as water deprivation duration increased, suggesting that dehydration caused a significant decrease in pain perception. Finally, the data described here clearly showed the implication of serotonin and dopamine neurotransmitter systems in the resistance to osmotic stress. Therefore, in this study, such central impairments were traduced by a few peripheral outcomes manifested by changes in mood state and nociception.

Acclimation to Water Restriction Implies Different Paces for Behavioral and Physiological Responses in a Lizard Species.

Chronic changes in climate conditions may select for acclimation responses in terrestrial animals living in fluctuating environments, and beneficial acclimation responses may be key to the resilience of these species to global changes. Despite evidence that climate warming induces changes in water availability, acclimation responses to water restriction are understudied compared with thermal acclimation. In addition, acclimation responses may involve different modes, paces, and trade-offs between physiological and behavioral traits. Here, we tested the dynamical acclimation responses of a dry-skinned terrestrial ectotherm to chronic water restriction. Yearling common lizards (Zootoca vivipara) were exposed to sublethal water restriction during 2 mo of the summer season in laboratory conditions, then released in outdoor conditions for 10 additional months. Candidate behavioral (exploration, basking, and thermal preferences) and physiological (metabolism at rest and standard water loss rate) traits potentially involved in the acclimation response were measured repeatedly during and after water restriction. We observed a sequential acclimation response in water-restricted animals (yearlings spent less time basking during the first weeks of water deprivation) that was followed by delayed sex-specific physiological consequences of the water restriction during the following months (thermal depression in males and lower standard evaporative water loss rates in females). Despite short-term negative effects of water restriction on body growth, annual growth, survival, and reproduction were not significantly different between water-restricted and control yearlings. This demonstrates that beneficial acclimation responses to water restriction involve both short-term flexible behavioral responses and delayed changes in thermal and water biology traits.

Sex- and age-dependent differences in the hormone and drinking responses to water deprivation.

Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.

Single-Cell RNA Sequencing Reveals Renal Endothelium Heterogeneity and Metabolic Adaptation to Water Deprivation.

BACKGROUND: Renal endothelial cells from glomerular, cortical, and medullary kidney compartments are exposed to different microenvironmental conditions and support specific kidney processes. However, the heterogeneous phenotypes of these cells remain incompletely inventoried. Osmotic homeostasis is vitally important for regulating cell volume and function, and in mammals, osmotic equilibrium is regulated through the countercurrent system in the renal medulla, where water exchange through endothelium occurs against an osmotic pressure gradient. Dehydration exposes medullary renal endothelial cells to extreme hyperosmolarity, and how these cells adapt to and survive in this hypertonic milieu is unknown. METHODS: We inventoried renal endothelial cell heterogeneity by single-cell RNA sequencing >40,000 mouse renal endothelial cells, and studied transcriptome changes during osmotic adaptation upon water deprivation. We validated our findings by immunostaining and functionally by targeting oxidative phosphorylation in a hyperosmolarity model in vitro and in dehydrated mice in vivo. RESULTS: We identified 24 renal endothelial cell phenotypes (of which eight were novel), highlighting extensive heterogeneity of these cells between and within the cortex, glomeruli, and medulla. In response to dehydration and hypertonicity, medullary renal endothelial cells upregulated the expression of genes involved in the hypoxia response, glycolysis, and-surprisingly-oxidative phosphorylation. Endothelial cells increased oxygen consumption when exposed to hyperosmolarity, whereas blocking oxidative phosphorylation compromised endothelial cell viability during hyperosmotic stress and impaired urine concentration during dehydration. CONCLUSIONS: This study provides a high-resolution atlas of the renal endothelium and highlights extensive renal endothelial cell phenotypic heterogeneity, as well as a previously unrecognized role of oxidative phosphorylation in the metabolic adaptation of medullary renal endothelial cells to water deprivation.

Reproductive state and water deprivation increase plasma corticosterone in a capital breeder.

Plasma corticosterone (CORT) concentrations fluctuate in response to homeostatic demands. CORT is widely recognized as an important hormone related to energy balance. However, far less attention has been given to the potential role of CORT in regulating salt and water balance or responding to osmotic imbalances. We examined the effects of reproductive and hydric states on CORT levels in breeding Children's pythons (Antaresia childreni), a species with substantial energetic and hydric costs associated with egg development. Using a 2 × 2 experimental design, we examined how reproduction and water deprivation, both separately and combined, impact CORT levels and how these changes correlate with hydration (plasma osmolality) and energy levels (blood glucose). We found that reproduction leads to increased CORT levels, as does dehydration induced by water deprivation. The combined impact of reproduction and water deprivation led to the largest increases in CORT levels. Additionally, we found significant positive relationships among CORT levels, plasma osmolality, and blood glucose. Our results provide evidence that both reproductive activity and increased plasma osmolality can lead to increased plasma CORT in an ectotherm, which could be explained by either CORT having a role as a mineralocorticoid or CORT being elevated as part of a stress response to resource imbalances.

A neural mechanism for deprivation state-specific expression of relevant memories in Drosophila.

Motivational states modulate how animals value sensory stimuli and engage in goal-directed behaviors. The motivational states of thirst and hunger are represented in the brain by shared and unique neuromodulatory systems. However, it is unclear how such systems interact to coordinate the expression of appropriate state-specific behavior. We show that the activity of two brain neurons expressing leucokinin neuropeptide is elevated in thirsty and hungry flies, and that leucokinin release is necessary for state-dependent expression of water- and sugar-seeking memories. Leucokinin inhibits two types of mushroom-body-innervating dopaminergic neurons (DANs) to promote thirst-specific water memory expression, whereas it activates other mushroom-body-innervating DANs to facilitate hunger-dependent sugar memory expression. Selection of hunger- or thirst-appropriate memory emerges from competition between leucokinin and other neuromodulatory hunger signals at the level of the DANs. Therefore, coordinated modulation of the dopaminergic system allows flies to prioritize the expression of the relevant state-dependent motivated behavior.

Role of dopamine D1-like and D2-like receptors in the activation of ingestive behaviour in thirsty rats licking for water.

RATIONALE: Analysis of lick pattern for sucrose and NaCl and of the forced swimming response after dopamine antagonist administration led us to suggest that dopamine on D1-like receptors is involved in behavioural activation, and the level of activation is "reboosted" on the basis of an evaluation process involving D2-like receptors. Although some studies investigated licking microstructure for water after dopamine antagonists, the within-session time course of their effect was never investigated. OBJECTIVES: The aims of this study were to further investigate the role of dopamine receptors in the mechanisms governing water ingestion, focussing on the within-session time course of the microstructure parameters, and to test the proposed hypothesis. MATERIALS AND METHODS: The effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01-0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025-0.25 mg/kg) on licking microstructure for water were examined in 20-h water-deprived rats in 30-min sessions. RESULTS: As previously observed with sucrose and NaCl, SCH 23390 reduced licking by reducing burst number, suggesting reduced behavioural activation. Moreover, it resulted in an increased burst size. Raclopride reduced the size of licking bursts, while their number was either increased or decreased depending on the dose. CONCLUSION: The results support the suggestion that D1 receptors are involved in behavioural activation and D2 receptors are involved in a related evaluation process. Within the framework of the proposed hypothesis, the increased burst size after D1-like receptor blockade might be interpreted as a pro-hedonic effect consequent to the increased cost of the activation of the licking response.

Impact of water restriction periods on carcass traits and meat quality of feedlot lambs in the Brazilian semi-arid region.

Water restriction periods were evaluated in crossbred lambs (n = 32) distributed in one of four treatments: without water restriction, water restriction for 24, 48 and 72 h. The water restriction for 72 h reduced the water and dry matter intakes, body weight at slaughter and hot and cold carcass yields. Water restriction did not affect the weight of the carcass cuts and the chemical composition of the meat. The fatty acid EPA increased and DHA reduced with increasing water restriction period. There was an increasing linear effect for meat shear force, with less force (30.5 N/cm2) for sheep meat without water restriction and higher force (45.8 N/cm2) for those with water restriction for 72 h. The period of 24 h of water restriction was the one that promoted the highest similarities in the characteristics assessed to those in animals receiving water ad libitum. Therefore, water restriction periods should not exceed 24 h for feedlot animals in situations of severe water shortage.

Water deprivation does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.

Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). The purpose of this study was to test the hypothesis that WD induces hypernatremia and consequently augments sympathetic and pressor responses to sympathoexcitatory stimuli in rats and humans. Sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to sciatic afferent nerve stimulation (2-20 Hz) and chemical stimulation of the rostral ventrolateral medulla (RVLM) were assessed in rats after 48 h of WD and compared with normally hydrated control rats (CON). In a parallel randomized-crossover human experiment (n = 13 healthy young adults), sympathetic (microneurography) and pressor (photoplethysmography) responses to static exercise were compared between 16-h WD and CON conditions. In rats, plasma [Na+] was significantly higher in WD versus CON [136 ± 2 vs. 144 ± 2 (SD) mM, P < 0.01], but sciatic afferent nerve stimulation produced similar increases in renal SNA [5 Hz, 174 ± 34 vs. 169 ± 49% (SD), n = 6-8] and mean ABP [5 Hz, 21 ± 6 vs. 18 ± 7 (SD mmHg, n = 6-8]. RVLM injection of l-glutamate also produced similar increases in SNA and ABP in WD versus CON rats. In humans, WD increased serum [Na+] [140.6 ± 2.1 vs. 142.1 ± 1.9 mM (SD), P = 0.02] but did not augment sympathetic [muscle SNA: change from baseline (Δ) 6 ± 7 vs. 5 ± 7 (SD) bursts/min, P = 0.83] or mean ABP [Δ 12 ± 5 vs. 11 ± 8 (SD) mmHg, P = 0.73; WD vs. CON for all results] responses during the final minute of exercise. These findings suggest that despite eliciting relative hypernatremia, WD does not augment sympathetic or pressor responses to sciatic afferent stimulation in rats or to static exercise in humans. NEW & NOTEWORTHY Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). We sought to determine whether plasma hypernatremia/hyperosmolality induced by WD augments sympathetic and pressor responses to sympathoexcitatory stimuli. Our findings suggest that WD does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.

Selected to survive and kill: Tityus serrulatus, the Brazilian yellow scorpion.

Annually, more than 1.2 million scorpion stings and more than 3,000 deaths occur worldwide. Tityus serrulatus Lutz and Mello, 1922 (Scorpiones, Buthidae) is the most medically relevant species in Brazil where it is spreading rapidly and causing over 90,000 cases of envenomation yearly. We monitored T. serrulatus longevity and ability to reproduce under conditions of food and/or water deprivation. We found that T. serrulatus is highly tolerant to food deprivation, with individuals enduring up to 400 days without food. On the other hand, access to water played a pivotal role in T. serrulatus survival. Food and water deprived scorpions showed weight reduction. Reproduction occurred throughout the year for food-deprived scorpions and controls, but not in the water-deprived groups. Remarkably, food-deprived animals were able to give birth after 209 days of starvation. Tityus serrulatus resistance to food and water deprivation is likely to be an additional factor underlying this species' geographic expansion and the difficulties encountered in controlling it.

Hedonic drinking engages a supraspinal inhibition of thermal nociception in adult rats.

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.

Oestradiol acts through its beta receptor to increase vasopressin neuronal activation and secretion induced by dehydration.

Vasopressinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei express oestrogen receptor (ER)ß and receive afferent projections from osmosensitive neurones that express ERα. However, which subtype of these receptors mediates the effects of oestradiol on vasopressin (AVP) secretion induced by hydromineral challenge has not yet been demonstrated in vivo. Moreover, AVP secretion induced by hyperosmolality is known to involve activation of TRPV1 (transient receptor potential vanilloid, member 1) in magnocellular neurones, although whether oestradiol modulates expression of this receptor is unknown. Thus, the present study aimed to clarify the mechanisms involved in the modulation exerted by oestradiol on AVP secretion, specifically investigating the involvement of ERß, ERα and TRPV1 receptors in response to water deprivation (WD). We observed that treatment with an ERß agonist potentiated AVP secretion and vasopressinergic neuronal activation induced by WD. This increase in AVP secretion induced by WD was reversed by an ERß antagonist. By contrast to ERß, the ERα agonist did not alter plasma AVP concentrations or activation of AVP neurones in the SON and PVN. Additionally, Fos expression in the subfornical organ was not altered by the ERα agonist. TRPV1 mRNA expression was increased by WD in the SON, although this response was not altered by any treatment. The results of the present study suggest that ERß mediates the effects of oestradiol on AVP secretion in response to WD, indicating that the effects of oestradiol occur directly in AVP neurones without affecting TRPV1.

A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).