Vasopressin Research Articles

Relationship between plasma urea and copeptin in response to arginine stimulation in healthy adults, patients with vasopressin deficiency and primary polydipsia

BackgroundArginine infusion stimulates copeptin secretion, a surrogate marker of arginine vasopressin (AVP), thereby serving as a diagnostic test in the differential diagnosis of suspected AVP deficiency (AVP-D). Yet, the precise mechanism underlying the stimulatory effect of arginine on the vasopressinergic system remains elusive. Arginine plays a significant role in the urea cycle and increases the production of urea. An increase in plasma urea concentration raises blood osmolality, thereby possibly stimulating AVP release. We therefore hypothesized that the stimulatory effect of arginine on AVP may involve an increase in plasma urea levels.MethodsThis analysis combined data from two prospective diagnostic studies. In total, 30 healthy adults (HA), 69 patients with AVP-D, and 89 patients with primary polydipsia (PP) underwent the arginine stimulation test. Infusion of arginine (L-­arginine­-hydrochloride 21%) at a dose of 0.5 g/kg body weight diluted in 500 mL of 0.9% normal saline was administered over 30 min. Blood was collected at baseline and 60, 90, and 120 min to analyze plasma copeptin and urea. The main objective was to investigate urea dynamics in response to arginine administration and its effect on copeptin release.ResultsPlasma urea levels at baseline were comparable and increased 60 min after arginine infusion with a median (IQR) change of + 1.1 mmol/L (+ 0.8, + 1.5) in HA, + 1.4 mmol/L (+ 1.1, + 1.7) in patients with AVP-D and + 1.3 mmol/L (+ 0.9, + 1.5) in patients with PP. Concurrently, plasma copeptin levels substantially increased 60 min from baseline in HA (median change + 5.3 pmol/L (+ 3.2, + 8.8)) and in patients with PP (median change + 2.4 pmol/L (+ 1.2, + 3.8)), but remained stable in patients with AVP-D (median change + 0.3 pmol/L (+ 0.1, + 0.6)). Plasma urea and copeptin levels correlated the most in HA, with a Spearman’s rho of 0.41 at baseline. Patients with AVP-D and PP showed only weak correlations of plasma urea and copeptin, with a correlation coefficient between 0.01 and 0.28.ConclusionWe demonstrate a slight increase in plasma urea levels in response to arginine, but plasma urea and copeptin levels were weakly correlated. Based on these findings, the stimulatory effect of arginine on AVP cannot be explained primarily by increasing urea levels.

Compensatory mechanisms underlying arginine vasopressin regulation in transient polyuria during pregnancy.

Transient polyuria during pregnancy is reportedly caused by increased arginine vasopressin (AVP) degradation due to vasopressinase produced by the placenta. The mechanism underlying transient polyuria during pregnancy has not been established. In this study we measured urine volume, urine osmolality, and AVP transcriptional activity during pregnancy in wild-type and familial neurohypophysial diabetes insipidus (FNDI) mice. The FNDI mice were used as a partial AVP deficiency model. Vasopressinase was shown to be present in the placentas of pregnant mice. The Avp hnRNA level in the supraoptic nucleus, which is indicative of AVP transcriptional activity, was upregulated in wild-type and FNDI mice during late pregnancy. FNDI mice, but not wild-type mice, had a significant increase in urine volume and a decrease in urine osmolality during pregnancy. These data suggest that an increase in urine volume during pregnancy only occurs when the compensatory increase in AVP release is insufficient to counteract degradation by vasopressinase.

Fluid and Electrolyte Disorders in Traumatic Brain Injury: Clinical Implications and Management Strategies

Traumatic brain injuries (TBIs) cause direct central nervous system injury. The presentation depends on the location, the type, and the severity of the injury. Additional injury may develop secondary to compression, the disruption of cerebral perfusion, and changes in sodium levels, resulting in either cellular edema or dehydration. Plasma osmolality (Posm) is a critical parameter influenced by solute concentrations, including sodium, glucose, and urea, and is a relevant concern when considering sodium levels in these patients. While Posm can be calculated using a standard formula, direct measurements via osmometry offer better accuracy. It is essential to differentiate between osmolality and tonicity; the latter refers specifically to effective solutes that drive water movement in the extracellular fluid. Sodium and its anions are effective solutes, whereas urea and glucose have variable effects due to their permeability and insulin dependence. Following TBI, the dysregulation of osmoregulation may occur and affect neurological outcomes. Osmoreceptors in the brain regulate arginine vasopressin secretion in response to changes in effective solute concentrations, with sodium chloride and mannitol being potent stimuli. The regulation of plasma osmolality, typically maintained within ±5% of the 280–295 mOsm/kg H2O range, is crucial for homeostasis and relies on antidiuresis and thirst mechanisms. This review narrative underscores the complexities of osmoregulation in the context of TBIs and their clinical implications, particularly concerning the development of conditions such as diabetes insipidus, the syndrome of inappropriate antidiuretic hormone secretion, and abnormal thirst.

Arginine vasopressin deficiency associated with accelerated phase myeloproliferative neoplasm with monosomy 7

Arginine vasopressin deficiency associated with accelerated phase myeloproliferative neoplasm with monosomy 7

Ribosomal s6 kinase (RSK) is a mediator of aquaporin-2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib.

Vasopressin (VP) activates protein kinase A (PKA), resulting in phosphorylation events and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as a major mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in collecting duct principal cells in rat kidneys. RSK inhibition with BI-D1870 blocked erlotinib-induced AQP2 serine 256 (S256) phosphorylation and membrane accumulation. CRISPR-generated RSK knockout cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro. Inhibition of PDK1, a known activator of RSK, blocked erlotinib-induced AQP2 S256 phosphorylation and membrane accumulation. We conclude that RSK is a crucial terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib.

Importance of early use of tolvaptan in hyponatremic acutely decompensated heart failure patients, a retrospective study

BackgroundHyponatremia is one of the complicating findings in acute decompensated heart failure. Decrease in cardiac output and systemic blood pressure triggers activation of renin–angiotensin–aldosterone system, antidiuretic hormone, and norepinephrine due to the perceived hypovolemia. Fluid-overloaded heart failure patients are commonly treated with loop diuretics, acutely decompensated heart failure patients tend to be less responsive to conventional oral doses of a loop diuretic, while other different diuretics could work in different part of nephron circulation system. In this study, we aim to further examine the role of tolvaptan, a vasopressin receptor antagonist, in the treatment of hyponatremia secondary to acutely decompensated heart failure.ResultsA total of 71 patients with hyponatremia secondary to ADHF were included, and all patients were given tolvaptan. 37 patients were administered tolvaptan early (up until 5 th day of admission). 34 patients received tolvaptan after 5 th day of admission mean administration as 6.86 th day, and median administration was 5 th day. Analysis showed lower length of stay in patients receiving early administration of tolvaptan compared to late administration (8.86 ± 5.06 vs 18.5 ± 9.05 p0.001, respectively). Patients with early initiation of tolvaptan also achieved a larger net increase in sodium levels at discharge compared to admission (6.46 ± 6.69 vs 3.68 ± 4.70 p0.048, respectively).ConclusionsEarly administration of tolvaptan in treating hyponatremia in acutely decompensated heart failure patients is associated with a lower length of hospitalization and a higher increase in serum sodium of patients in hyponatremic ADHF patients.

Endocrine Outcome and Quality of Life After Transsphenoidal Resection of Pituitary Adenoma-A Prospective Randomized Single-Blinded Study Comparing Endoscopic Versus Microscopic Resection.

Endoscopic pituitary surgery might yield better endocrine outcomes compared to microscopic resection. We conducted a prospective, randomized, single-blinded study to compare the endocrine outcome and quality of life (QoL) of patients with newly diagnosed pituitary adenoma who underwent either endoscopic or microscopic transsphenoidal surgery (NCT03515603). Due to slow recruitment, this study had to be stopped prematurely. Out of 170 transsphenoidal pituitary surgeries performed during the study period, 36 patients were enrolled in this study. The primary endpoint was based on the development of a new hypopituitarism. Secondary endpoints included the extent of resection, complications, and QoL. Endoscopic surgery was performed in 47.2% (n = 17). A new hypopituitarism was found in 8.3% (n = 3). All these cases underwent microscopic resection. Arginine vasopressin deficiency was found in 2.7% (n = 1) after microscopic resection. Gross total resection was achieved in 94.4% (n = 34). No surgical complications or new neurological deficits were observed. QoL improved significantly after the surgery, as measured by EQ-VAS (p = 0.003). According to EQ-5D3L, QoL improved or remained unchanged in almost all patients. No significant difference was found in QoL between the endoscopic and microscopic groups. The endoscopic technique appears to offer benefits in the treatment of pituitary adenomas, particularly in terms of achieving a favorable endocrine outcome.

Hyponatraemia-induced Takotsubo syndrome secondary to idiopathic syndrome of inappropriate antidiuretic hormone: a case report

Hyponatraemia-induced Takotsubo syndrome secondary to idiopathic syndrome of inappropriate antidiuretic hormone: a case report

What's the Gut Doing in the Chest? Interpositio Hepatodiaphragmatica (Chilaiditi Sign) Revisited on 18F-FDG PET/CT.

A 47-year-old woman, a diagnosed case of syndrome of inappropriate secretion of antidiuretic hormone, underwent 18F-FDG PET/CT to detect occult malignancy for suspected paraneoplastic etiology. Abnormal FDG uptake was noted in the right lower chest region, which was correlated on corresponding CT images to be colonic activity interposed between the liver and elevated diaphragm, also known as Chilaiditi sign. Even though rare, Chilaiditi sign should be considered as a differential diagnosis of hypermetabolic activity in the right lower chest region on 18F-FDG PET/CT scan that is done to look for occult tumor as shown in this case.

Cushing Disease Clinical Phenotype and Tumor Behavior Vary With Age: Diagnostic and Perioperative Implications

Abstract Context Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing disease (CD) with aging. Objective Using a large multi-institutional data set, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes. Methods Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications. Results Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78 years). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and adrenocorticotropin nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age. Conclusion There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classic phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes.

Hormonal mechanisms in the paraventricular nuclei associated with hyperalgesia in Parkinson's disease model rats.

Pain is a major non-motor symptom of Parkinson's disease (PD). The relationship between hyperalgesia and neuropeptides originating from paraventricular nucleus (PVN) in 6-hydroxydopamine (6-OHDA) rats has already been investigated for oxytocin (OXT), but not yet for arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH). The present study aimed to investigate the alterations in these neuropeptides following nociceptive stimulation in PD model rats and to examine the mechanisms of hyperalgesia. Dopaminergic nigrostriatal lesions were induced by injecting 6-OHDA into the medial forebrain bundle. Subcutaneous formalin injection into the vibrissa pad was performed in rats as a nociceptive stimulus in the orofacial region. Dopamine depletion's effect on nociception was assessed by counting the p-ERK-immunoreactive (-IR) cells in the trigeminal spinal subnucleus caudalis (Vc). The PD model rats induced by 6-OHDA injection (6-OHDA rats) showed a significantly higher number of p-ERK-IR cells in the Vc than the sham rats, confirming hyperalgesia in 6-OHDA rats. Then, we investigated the immunohistochemical responses to OXT, AVP, and CRH cells in the PVN and examined the changes in blood levels of these neuropeptides. As a result, formalin injection increased neuronal activity and blood levels of OXT and CRH in sham rats, but these were suppressed in the 6-OHDA rats. Contrarily, neuronal activity and blood level of AVP were unaffected by nociceptive stimuli and were significantly lower in 6-OHDA rats than in sham rats. Our findings suggest that OXT and CRH suppression is linked to hyperalgesia in PD, whereas AVP does not directly influence the observed hyperalgesia.

Serum Antidiuretic Hormone Level in Nocturnal Enuretic School Children in a Tertiary Care Hospital in Bangladesh: A Cross-Sectional Study.

Primary nocturnal enuresis (PNE) is a common pediatric condition characterized by involuntary nighttime bed wetting. Primary monosymptomatic nocturnal enuresis (PMNE) is associated with altered antidiuretic hormone (ADH) secretion and lacks lower urinary tract symptoms. This study aimed to compare serum ADH levels between children with PMNE and a comparison group to explore its potential role in the pathophysiology of PMNE. This cross-sectional study included 40 children aged 6-15 years with PMNE and 40 age-matched children without enuresis (comparison group) attending the Pediatric Nephrology Outpatient Department at the National Institute of Kidney Diseases and Urology (NIKDU) from January 2022 to July 2023. Blood samples and other clinical information along with laboratory investigation are done to ensure inclusion and exclusion criteria. Fasting serum ADH level, a competitive immunoassay was done with the Arg- Vasopressin ELISA kit. Relevant clinical and demographic data were analyzed using Student's t-test for continuous variables and Chi-square/Fisher's exact tests for categorical variables. The mean age of participants was 8.82 ± 2.71 years in the PMNE group and 9.01 ± 2.54 years in the comparison group (p = 0.760). There was no significant association between sex and PMNE (p = 0.370). Children with PMNE exhibited significantly lower serum ADH levels compared to the comparison group (p < 0.05). Additionally, children with more frequent enuretic episodes demonstrated a trend of lower ADH levels (p < 0.05). This study provides evidence of a significant association between decreased diurnal serum ADH levels and PNE in children. These findings contribute to a better understanding of the pathophysiology of PNE and suggest potential avenues for novel treatment strategies, emphasizing the importance of evaluating ADH levels in PNE management.

Orally administered prednisolone decreases plasma arginine vasopressin and serum copeptin concentrations in healthy dogs.

The pathophysiology of polyuria and polydipsia secondary to exogenous glucocorticoid excess is incompletely understood. Investigate plasma AVP (pAVP) and serum CoP (sCoP) concentrations in healthy dogs before, during, and after abrupt discontinuation of a long-term course of orally administered prednisolone. Eight healthy neutered young adult research Beagles. In our prospective longitudinal study, Beagles were treated with a placebo PO q24h for 15 days (baseline), followed by a 35-day course of prednisolone (2.35-2.75 mg/kg PO q24h) and then abrupt discontinuation of prednisolone. Serial pAVP and sCoP concentrations, urine specific gravity (USG) and calculated plasma osmolality (pOsmcalculated) were determined during placebo and prednisolone administration, and up to 4 weeks after prednisolone discontinuation. Paired plasma samples for pAVP measurement were obtained in EDTA tubes with (pAVPP800) and without (pAVPEDTA) a proprietary combination of protease, esterase, and dipeptidyl peptidase-IV inhibitors (BD Biosciences P800). Mean pAVPP800 and sCoP concentrations were significantly lower at the end of the prednisolone course (25.8 ± 8.1 pg/mLand 166 pg/mL, range, 131-223) vs baseline (34.1 ± 5.4 pg/mL and 243 pg/mL, range, 157-336; P = .02, P = .02, respectively). Correlations between pAVPP800 and sCoP (r = .77, P = .001) and pAVPP800 and USG (r = .61, P = .02) were positive, despite no correlation between pAVPP800 and pOsmcalculated, sCoP and pOsmcalculated, and sCoP and USG. On paired samples, mean pAVPEDTA was significantly lower (5.0 ± 2.5 pg/mL) than mean pAVPP800 (34.1 ± 5.4 pg/mL; P < .0001). Orally administered prednisolone led to markedly decreased plasma AVP and serum CoP concentrations despite increased calculated plasma osmolality and stable systolic blood pressure.

Alpha-Gal-KO Xenothymokidney Response to Endogenous Arginine Vasopressin in a Living Human Recipient with a Durable Mechanical Circulatory Support Device

Alpha-Gal-KO Xenothymokidney Response to Endogenous Arginine Vasopressin in a Living Human Recipient with a Durable Mechanical Circulatory Support Device

Cerebral salt wasting syndrome following a traumatic frontal lobe hematoma : A case report

BACKGROUND Cerebral Salt Wasting Syndrome (CSWS) is a rare complication of intracranial pathology characterized by hyponatremia and extracellular volume depletion. It is often confused with other sodium and water balance disorders, such as Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and Central Diabetes Insipidus (CDI), making early diagnosis and appropriate management crucial. CASE PRESENTATION We present the case of a 68-year-old male with type 2 diabetes mellitus who suffered a traumatic frontal lobe hemorrhagic contusion following a fall. The patient developed polyuria and hyponatremia on the 6th day of admission, initially misdiagnosed as CDI and treated with desmopressin. However, despite treatment, his urine output continued to rise, and hyponatremia persisted. Subsequent evaluations, including urine and serum osmolarity, high urinary sodium levels, and imaging studies, led to the diagnosis of CSWS. Treatment was adjusted to include intravenous isotonic saline and fludrocortisone, significantly reducing urine output and correcting serum sodium levels. The patient was successfully discharged on the 25th day with stable electrolyte levels. CONCLUSION This case highlights the diagnostic challenges in differentiating CSWS from other sodium balance disorders, particularly CDI, in patients with traumatic brain injury. It emphasizes the importance of careful monitoring of urine and serum biochemistry, fluid status, and clinical progression to ensure accurate diagnosis and effective management. Early recognition and appropriate therapy for CSWS, including sodium and fluid replacement, can prevent further complications and improve patient outcomes.

Hyponatremia in Neurosurgical Patients

Hyponatremia refers to a common and potentially dangerous electrolyte imbalance observed in neurosurgical patients, particularly following traumatic brain injuries, subarachnoid hemorrhages, brain tumors, and pituitary surgeries. The paper discusses primary causes and pathophysiology of hyponatremia, including the syndrome of inappropriate secretion of antidiuretic hormone, central adrenal insufficiency, and cerebral salt wasting syndrome. The paper presents differential diagnostic approaches for accurately identifying the underlying causes of hyponatremia, as well as therapeutic strategies that include hypertonic sodium solution infusions, hydrocortisone replacement therapy, and the use of vasopressin receptor antagonists. The study delineates the potential complications associated with overly rapid correction of sodium levels, such as osmotic demyelination syndrome. It emphasizes the importance of accurate diagnosis and timely treatment to enhance patient outcomes and minimize the risk of complications.

Analyzing the adverse events of NK-1 receptor antagonists: a pharmacovigilance study from the FAERS database

BackgroundNK-1 receptor antagonists (NK-1RAs) are proven to be successful in preventing chemotherapy-induced nausea and vomiting (CINV). The safety profile of NK-1RAs has not been systematically analyzed in the real world. This pharmacovigilance study investigated the differences in adverse events (AEs) between NK-1RAs.MethodsAdverse events (AEs) associated with NK-1RAs were gathered and standardized using data from the FAERS database spanning from the first quarter of 2009 to the fourth quarter of 2023. Various disproportionality techniques were employed for data analysis, such as the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).ResultsA total of 5434AE reports listing NK-1RAs as the primary suspected drugs were identified. The System Organ Classes (SOC) appeared as significant safety signals were found. Among NK-1RAs, the most frequently reported AEs were related to general disorders and administration site conditions. In terms of PT level, the strong signals were mainly injection site reactions associated with aprepitant and fosaprepitant. Moreover, toxic encephalopathy and encephalopathy of the aprepitant were all positive with four algorithms. A significant finding was the recognition of adverse events linked to endocrine disorders, which were not previously mentioned in the medication instructions.ConclusionThe safety profile of NK-1RAs has been reported to be variable.If intravenous formulations were used in the clinic, injection site reactions should be a concern. In addition, more attention should be paid to the management of encephalopathy toxicity in patients treated with aprepitant in combination with ifosfamide. Besides known AEs, we have identified several new high-risk AEs, such as inappropriate antidiuretic hormone secretion, adrenal insufficiency and hyponatraemia. Overall, clinicians should closely monitor the occurrence of NK-1RA-related AEs in clinical applications.

The Different Paths That Lead to Hypotonic Hyponatremia, and a Safe Approach to Treatment.

A knowledge gap may exist when attempting to identify the pathogenetic mechanisms resulting in the syndrome of inappropriate antidiuretic hormone (SIADH) or hypotonic hyponatremia. Ectopic secretion of antidiuretic hormone [ADH] is the classic cause of SIADH. But another form of inappropriate secretion of ADH occurs when interleukin 6 is activated. Hypotonic hyponatremia can also occur in patients with cerebral salt wasting, but the secretion of ADH is appropriate, responding to volume depletion induced by excessive natriuresis. Reset osmostat (RO) is another cause of hypotonic hyponatremia caused by an unknown anomaly in the hypothalamus. This review discusses the pathophysiology of and the identical laboratory findings found in classic ectopic ADH secretion, interleukin 6-mediated ADH secretion, cerebral salt wasting-induced ADH secretion, and RO. This review also discusses potential methods to discern which hypotonic hyponatremic syndrome is present and current recommendations for treatment.

Central regulation of drinking water in divergently selected high-water-efficient young broiler chickens: A minireview.

Poultry production is confronting real challenges, including a lofty projected high demand for animal proteins to feed the future, and the need to adapt to planetary boundaries (global warming) with limited natural resources (land, energy, water). Among the most challenging stressors to poultry production sustainability are heat stress (HS) and water uncertainty, that need extensive fundamental and applied research to identify effective strategies. In that regard, our group has recently developed a high-water-efficient broiler (meat-type) chicken line using water conversion ratio (WCR) as a phenotypic trait and defined the hypothalamic molecular mechanisms controlling drinking water under heat stress conditions. In response to the invitation from the Organizing Committee of the 13th International Symposium on Avian Endocrinology (ISAE 2024), the present review summarizes these data and closes the chapter by asking questions for future investigations. Data showed that HS exposure increased core body temperature (CBT) of both lines, with higher degree in HWE than in LWE counterparts. Despite this increase in CBT, HWE line drank less water but had superior performance with better feed conversion ratio (FCR) and WCR than LWE line. Molecular analyses showed that hypothalamic drinking-related neuropeptides (arginine vasopressin system, aquaporin system, renin, and angiotensin system) are affected in line- and/or environmental-dependent manner. Together, our research outcome indicates that the divergent selection for water efficiency could be an effective strategy to preserve water while maintaining optimal growth performance and could be applied to other poultry species and livestock.

The jeong and haan of Vincent van Gogh: neuropeptides of bondedness and loss.

We introduce two Korean-named yet transcultural feelings, jeong and haan, to fill gaps in neuroscientific understanding of mammalian bondedness, loss, and aggression. Jeong is a visceral sense of connectedness to a person, place, or thing that may arise after proximity, yet does not require intimacy. The brain opioid theory of social attachment (BOTSA) supports the idea that jeong involves increased activity of enkephalins and beta-endorphins. We propose that withdrawal of jeong-related neuropeptides leads to original haan, a sense of "missingness" that is too subtle to be grossly dysphoric. Through narrative, cognitive appraisals, or moral assignments, however, original haan may transform into the feeling of constructed haan-resentment, bitterness, grievance, sorrow, or suppressed anger. In males, the transformation may be driven by arginine vasopressin, an ancient fight-or-flight neurohormone. Constructed haan may also be driven by vasopressin in females, though data is more sparse, and in both sexes it may depend on situational or societal context. Endogenous opioids inhibit vasopressin, so that when jeong diminishes, vasopressin release may become disinhibited. This relationship implies a companion to the BOTSA, which we articulate as the brain opioid and vasopressin theory of original and constructed haan (BOVTOCH). To illustrate, we reflect on borderline personality disorder, and Vincent van Gogh's self-severing of his ear while living and working with Paul Gauguin, and fearing abandonment by him; yet to understand Van Gogh more completely we also present the brain opioid theory of stable euphoric creativity (BOTSEC), to model the subjective "highs" associated with creative flow states. Together these brain opioid theories may help to explain how feelings related to social bondedness can influence a range of phenomena. For example, opioid drug dependence may be, at least partly, a maladaptive response to feelings of isolation or disconnectedness; the health protective effects of social bonds could be related to tonic exposure to endogenous opioids and their anti-inflammatory properties; endogenous opioid-based social relational enhancement may contribute to placebo responding. Finally we conclude by pointing out the possibility of virtuous cycles of social connectedness and creativity, when feelings of bondedness and euphoric flow reinforce one another through endogenous opioid elevation.