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At least 1,243 records · Page 69Linked to original sources
PubMed2004

Lithospermic acid B isolated from Salvia miltiorrhiza ameliorates ischemia/reperfusion-induced renal injury in rats.

The present study was designed to examine whether lithospermic acid B (LSB) isolated from Salvia miltiorrhiza has an ameliorative effect on renal functional parameters in association with the expression of aquaporin 2 (AQP 2) and Na,K-ATPase in the ischemia-reperfusion induced acute renal failure (ARF) rats. LSB showed strong antioxidant activity against production of reactive oxygen species (ROS), ROS-induced hemolysis, and production of lipid peroxide in a dose-dependent manner. Polyuria caused by down-regulation of renal AQP 2 in the ischemia-reperfusion induced ARF rats was partially restored by administration of LSB (40 mg/kg, i.p.), restoring expression of AQP 2, in renal inner and outer medulla. The expression of Na,K-ATPase alpha1 subunit in outer medulla of the ARF rats was also restored in the ARF rats by administration of LSB, while beta1 subunit level was not altered. The renal functional parameters including creatinine clearance, urinary sodium excretion, urinary osmolality, and solute-free reabsorption were also partially restored in ischemia-ARF rats by administration of LSB. Histological study also showed that renal damages in the ARF rats were abrogated by administration of LSB. Taken together, these data indicate that LSB ameliorates renal defects in rats with ischemia-reperfusion induced ARF, most likely via scavenging of ROS.

Acute Kidney Injury↗
PubMed2005

Naringenin attenuates cisplatin nephrotoxicity in rats.

The effect of naringenin (NAR), a naturally occurring citrus flavanone, on the acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5 days before cisplatin single i.v. injection, produced significant protection of renal function. NAR reduced the extent of cisplatin-induced nephrotoxicity, as evidenced by significant reduction in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione S-transferase (GST) activity, and increased creatinine clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and GST activity were markedly improved by NAR. Cisplatin-induced alterations in renal cortex antioxidant defense system were greatly prevented by NAR. In cisplatin-NAR combined treatment group, antioxidant enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin treated group. Platinum renal content was not affected by NAR treatment. The results provide further insight into the mechanisms of cisplatin-induced nephrotoxicity and confirm the antioxidant potential of NAR.

Animals↗
PubMed2006

[Nephrogenic diabetes insipidus].

Nephrogenic diabetes insipidus which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine-vasopressine (AVP). Polyuria, with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. Hypercalcemia, hypokaliemia, lithium administration and chronic renal failure are the principal causes of acquired nephrogenic diabetes insipidus. About 90 percent of patients with congenital nephrogenic diabetes insipidus are males with X-linked recessive nephrogenic diabetes insipidus who have mutations in the arginine-vasopressin receptor 2 (AVPR2) gene that codes for the vasopressin V2 receptor. The gene is located in chromosome region Xq28. In about 10 percent of the families studied, congenital nephrogenic diabetes insipidus has an autosomal recessive or autosomal dominant mode of inheritance. In these cases, mutations have been identified in the aquaporin-2 gene (AQP2), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and Cystinosis. Identification of the molecular defect underlying congenital nephrogenic diabetes insipidus is of immediate clinical significance because early diagnosis and treatment of affected infants can avert the physical and mental retardation associated with episodes of dehydration.

Diabetes Insipidus, Nephrogenic↗
PubMed2006

Cerebral venous thrombosis as a first presentation of diabetes.

This report presents a case of cerebral venous thrombosis and venous infarction in a diabetic patient, the third in the world literature (the second in a child). An 8-year-old male was admitted to the hospital due to abdominal pain, vomiting, polydypsia, and polyuria, lasting for 4 days. Laboratory studies revealed marked hyperglycemia and ketoacidosis. Two hours after admission the child lost consciousness. Emergency computed tomography performed 3 hours after admission (4 days after the onset of symptoms) revealed hyperdensity in the vein of Galen and superior sagittal sinus, consistent with thrombosis, accompanied by bilateral venous infarction. Follow-up computed tomography performed 6 days after admission (10 days after the onset of symptoms) documented evolution of thrombosis. Magnetic resonance imaging and magnetic resonance venography performed 22 days after admission (26 days after the onset of symptoms) confirmed venous infarction and thrombosis. This report discusses possible mechanisms of cerebral venous thrombosis in diabetic hyperglycemia and stresses the importance of imaging studies despite the extreme rarity of such cases.

Cerebral Infarction↗
PubMed2006

Emergencies in diabetic patients in the primary care setting.

The diabetic patient poses special problems in the primary care setting. Symptoms that are relatively unimpressive on initial presentation, such as polyuria or dizziness, may actually be the beginning of serious medical complications. With careful evaluation and follow-up, some patients, such as those who have mild hypo- and hyperglycemia and certain infections, can be managed as an outpatients; however, many cardiovascular conditions, such as cardiac ischemia or limb-threatening peripheral vascular disease, require immediate transfer to an acute care facility. In all situations, close monitoring of glucose levels during all phases of care--in the office, in the hospital and at home--is essential to achieving target glycemic control and rapid detection of clinical conditions that often first manifest as alterations in glycemic control.

Blood Glucose↗
PubMed2004

Inflammatory pseudotumor of the pituitary: case report.

BACKGROUND: Inflammatory pseudotumor of the pituitary is a very rare nonneoplastic lesion. We describe a case of a patient with past history of lymphocytic meningitis. CASE DESCRIPTION: A 32-year-old man presented with polyuria, polydipsia, anorexia, abdominal discomfort, and panhypopituitarism. He had 2 episodes of lymphocytic meningitis in the last two years. Magnetic resonance image (MRI) disclosed a sellar and suprasellar mass with extension to the pituitary stalk. The patient underwent transnasal-transsphenoidal surgery to remove the lesion. Histopathological findings revealed mixed inflammatory cells composed mainly of lymphocytes, macrophages and extensive fibrosis. CONCLUSIONS: Inflammatory pseudotumor of the pituitary, although rare, should be included in the differential diagnosis of a sellar and suprasellar mass.

Adult↗
PubMed2006

Colchicine antimitosis causes progression of S-(1,2-dichlorovinyl)-L-cysteine-induced injury leading to acute renal failure and death in mice.

Objective of the present study was to test the importance of tissue repair in the final outcome of S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced nephrotoxicity using colchicine (CLC) intervention. Male Swiss Webster (SW) mice were administered a normally nonlethal dose of DCVC (30 mg/kg, i.p.) on day 0 and CLC (2 mg/kg, i.p.) at 42 and 66 h after administration of DCVC. The mice were observed for mortality and various renal injury and repair parameters were studied during a time course of 0-14 days. Administration of 30 mg DCVC/kg led to loss of renal architecture by day 1, which sustained until day 5, and regressed thereafter to reach normal architecture by day 10 resulting in 100% survival. Renal dysfunction as assessed by increases in plasma BUN and creatinine levels was concordant during this time course. Urinary volume increased significantly between days 10 and 14 with significant increases in urinary glucose concentrations on days 1-4. Calpain leakage increased from day 1 and remained so until day 5 before declining at later time points. In contrast, CLC intervention led to marked inhibition of S-phase DNA synthesis and 100% mortality by 120 h. H&E sections of kidneys revealed loss of renal architecture on day 1 which progressively worsened from day 2 to 4. Polyuria and glycosuria were evident during the first 2 and 3 days, respectively. Calpain immunohistochemistry revealed progressive leakage of calpain in the extracellular space during 2-4 days which lead to increased renal injury as evident from significant increases in calpain specific breakdown products (CSBPs) of alpha-fodrin during the same period of time. The group of mice receiving 2 mg CLC/kg alone showed a significant increase in urinary creatinine concentration on day 5. Neither the expression nor localization of aquaporin 1 was altered in any of the treatment groups. These results show that antimitotic intervention after DCVC-initiated renal injury leads to expansion and progression of that injury, which appears to be due to proteolytic destruction of neighboring cells mediated by calpain leaking out of necrosed renal tubular epithelial cells.

Acute Kidney Injury↗
PubMed2004

Histopathological changes and inflammatory response induced by Tityus discrepans scorpion venom in rams.

Anesthetized rams envenomed s.c. with 40 microg/kg Tityus discrepans scorpion venom developed fasciculation, hypothermia, polyuria, pulmonary wet rales, tachypnea, respiratory distress and arrhythmia. Rams developed a cascade of inflammation reactions, characterized by activation of macrophages, fibroblasts and neutrophils, neutrophil infiltration and aggregation, vasculitis, arteritis and abundant fibrin deposition. At the inoculation site, venom was detected by immunohistochemistry in the extra cellular matrix, lymphatic vessels' and venules' lumen, inside macrophages and surrounding nerves. Extra cellular matrix was degraded at the inoculation site perhaps by activated neutrophils. Envenoming produced hepatocytes with Mallory body-like vacuoles which may be due to the increased plasmatic levels of TNF-alpha and IL6. Venom produced degranulation and vacuolization of acinary cells as well as interstitial swelling and necrosis. Necrosis of the Langerhan's islets occurred occasionally. Lungs showed the most deleterious effects developing wall collapse and necrosis, diffuse injury of the alveolar capillary barrier, interstitial and alveolar fibrin deposits with strong neutrophil infiltration. Massive infiltration of lymphocytes and macrophage occurred in the intestinal submucose, to the point that it modified villi and intestinal folding morphology. Envenomation developed a marked leukocyte aggregation surrounding nerves at the inoculation site. This study reveals that beyond its neurotoxicity, Tityus venom produces a severe and widespread inflammatory syndrome, expressed as histopathological changes at the site of inoculation, as well as in remote organs such as pancreas, lungs, intestine and liver. Our results suggest that not all remote targets are directly affected by the venom but that, as proposed earlier, are modified by inflammation by products produced elsewhere.

Animals↗
PubMed2006

Multifactorial nature of male nocturia.

OBJECTIVES: To conduct a prospective study to determine the causes of nocturia in men. METHODS: The study included 41 male patients (mean age 72.5 years) bothered by nocturia (two or more micturitions per night). Eleven asymptomatic young men (mean age 28.4 years) were enrolled as a control group. All completed a 3-day voiding diary. Daytime and nighttime urine samples were collected to determine osmolality and sodium and potassium levels. Urodynamic studies were performed for all patients with nocturia to evaluate for bladder outlet obstruction using the International Continence Society definition. Polysomnography was performed on selected patients to detect sleep apnea. RESULTS: The average nighttime voiding frequency was 3.9 in the patients with nocturia. Nocturnal polyuria (NP) was found in 34 (82.9%) of 41 patients. In these patients, the nighttime urinary sodium excretion was significantly greater than the daytime excretion, with lower nighttime urine osmolality. In contrast, nighttime and daytime sodium excretion was not significantly different in patients without NP, and greater nighttime urine osmolality was noted in the patients without NP and the control group. Of the 41 patients, 24 (58.5%) had a small nocturnal bladder capacity, with detrusor overactivity in 14 of 24 patients. Eighteen patients (43.9%) had both NP and a small nocturnal bladder capacity. Another 18 patients had bladder outlet obstruction and NP. Two patients had sleep apnea. CONCLUSIONS: Our observations have shown that a significant contributor to male nocturia is NP, which results from a disordered diurnal rhythm of sodium excretion and other unknown factors causing nocturnal urinary dilution. However, male nocturia can also be secondary to a combination of factors. Detailed workup is necessary to elucidate all causes.

Adult↗
PubMed1984

Potassium homeostasis and clinical implications.

The clinical estimation of potassium balance generally depends on the level of serum potassium. Since the extracellular fluid contains only 2 percent of the total body potassium, it must be recognized that potassium deficits are usually large before significant hypokalemia occurs, whereas smaller surfeits of potassium will cause hyperkalemia. The total body potassium is regulated by the kidney in which distal nephron secretion of potassium into the urine is enhanced by aldosterone, alkalosis, adaptation to a high potassium diet, and delivery of increased sodium and tubular fluid to the distal tubule. However, the distribution of potassium between the intracellular and extracellular fluids can markedly affect the serum potassium level without a change in total body potassium. Cellular uptake of potassium is regulated by insulin, acid-base status, aldosterone, and adrenergic activity. Hypokalemia, therefore, may be caused by redistribution of potassium into cells due to factors that increase cellular potassium uptake, in addition to total body depletion of potassium due to renal, gastrointestinal, or sweat losses. Similarly hyperkalemia may be caused by redistribution of potassium from the intracellular to the extracellular fluid due to factors that impair cellular uptake of potassium, in addition to retention of potassium due to decreased renal excretion. An understanding of the drugs that affect potassium homeostasis, either by altering the renal excretion of potassium or by modifying its distribution, is essential to the proper assessment of many clinical potassium abnormalities. Both hypokalemia and hyperkalemia may cause asymptomatic electrocardiographic changes, serious arrhythmias, muscle weakness, and death. Hypokalemia has also been associated with several other consequences, including postural hypotension, potentiation of digitalis toxicity, confusional states, glucose intolerance, polyuria, metabolic alkalosis, sodium retention, rhabdomyolysis, intestinal ileus, and decreased gastric motility and acid secretion.

Acid-Base Equilibrium↗
PubMed1997

Hyperuricemia as a clue for central diabetes insipidus (lack of V1 effect) in the differential diagnosis of polydipsia.

PURPOSE: In the differential diagnosis of patients with polyuria-polydipsia one must distinguish usually between primary polydipsia (PP) and central diabetes insipidus (CDI). The first situation is a state of volume expansion and the second of volume contraction. We evaluate whether serum uric acid determination could help to differentiate between the two conditions. PATIENTS AND METHODS: We analyzed the score of 13 consecutive patients with CDI, 7 patients with PP, and 7 patients with nephrogenic diabetes insipidus (NDI). Serum uric acid concentration was available during normonatremia without treatment with 1-desamino-8-D-arginine vasopressin (dDAVP), during mild dehydration and during treatment with dDAVP. In 8 of these patients plasma renin activity (PRA), urate, urea and creatinine clearances were also available. These data were also obtained in the patients with NDI. In 1 patient with CDI, we studied the effect on urate clearance of dDAVP, which stimulates exclusively the V2 receptors, and of triglycyl-lysine-vasopressin (TGLV), a potent V1-receptor agonist. RESULTS: Normonatremic polydypsic patients with CDI presented an increase in uric acid concentration (7.1 +/- 2.2 mg/dL), whereas in the PP group the value was decreased (3 +/- 0.75 mg/dL; P <0.001). All the normonatremic PP presented a serum uric acid concentration lower than 5 mg/dL, whereas all the normonatremic CDI patients, exept 1, presented a value higher than 5 mg/dL. In both groups blood urea concentration was decreased as a consequence of high renal clearances. The hyperuricemia of CDI was related to low uric acid clearances. Patients with hypernatremia and NDI presented a lower increase in serum uric acid concentration than those with similar levels of hypernatremia and CDI (NDI: 5.7 +/- 0.8 mg/dL and CDI: 7.9 +/- 2.3 mg/dL; P <0.05) and the NDI patients presented an urate clearance corrected for creatinine clearance which was significantly higher than in CDI (9% +/- 3% and 4% +/- 1.1%; P <0.01). When the patients with CDI were treated with dDAVP and normalyzed their PRA (0.9 +/- 0.4 ng/mL/h) we observed still mild hyperuricemia compared to controls (5.5 +/- 1.4 mg/dL and 4.3 +/- 0.9 mg/dL; P <0.01) and a low fractional excretion of filtered uric acid (6.5% +/- 1.7% compared to 8.2% +/- 2% in controls; P <0.05). Acute administration of dDAVP, stimulating the V2 receptors, in one patient with CDI, had no effect on urate clerance, while TGLV, which stimulates the V1 receptor, increased urate clearance. CONCLUSION: The presence of an serum uric acid concentration higher than 5 mg/dL in polyuric polydipsic patients is highly suggestive of CDI. Even when these patients are treated with dDAVP many of them remain hyperuricemic, and this seems to be the consequence of a lack of V1 receptor stimulation.

Adult↗
PubMed1998

Nephrogenic diabetes insipidus.

In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital nephrogenic diabetes insipidus (NDI), the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In <10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations of the aquaporin-2 gene (AQP2), ie, the vasopressin-sensitive water channel, have been identified. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind AVP or to trigger an intracellular cyclic adenosine-monophosphate (cAMP) signal. Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. The acquired form of NDI is much more common than the congenital form, is almost always less severe, and is associated with downregulation of AQP2. The advances described here are examples of "bedside physiology" and provide diagnostic tools for physicians caring for these patients.

Aquaporins↗
PubMed2000

Twin-to-twin transfusion syndrome. Role of the fetal renin-angiotensin system.

The twin-to-twin transfusion syndrome (TTS) results from an unbalanced blood supply through placental anastomoses in monochorionic twins. It induces growth restriction, renal tubular dysgenesis, and oliguria in the donor and visceromegaly and polyuria in the recipient. A better understanding of its pathophysiology could contribute to improving the management of TTS, which still carries a high perinatal mortality in both twins. As well as several other candidates, the renin-angiotensin system might be involved in TTS. To evaluate its role in the pathogenesis of the syndrome, we studied the kidneys of 21 twin pairs who died from TTS at 19 to 30 weeks, compared with 39 individuals in a control group, using light microscopy, immunohistochemistry, and in situ hybridization. The overexpression of the renin protein and transcript with frequent evidence of renin synthesis by mesangial cells was observed in the donor kidneys, presumably as a consequence of chronic renal hypoperfusion. This upregulation of renin synthesis might be beneficial to restore euvolemia. In severe cases of TTS, however, angiotensin-II-induced vasoconstriction acts as an additional deleterious factor by further reducing the renal blood flow in donors. In recipients, renin expression was virtually absent, possibly because it was down-regulated by hypervolemia. However, in addition to congestion and hemorrhagic infarction, there were severe glomerular and arterial lesions resembling those observed in polycythemia- or hypertension-induced microangiopathy. We speculate that fetal hypertension in the recipient might be partly mediated by the transfer of circulating renin produced by the donor, through the placental vascular shunts.

Female↗
PubMed2006

[Panhypopituitarism revealing metastasis of small-cell lung carcinoma associated with sarcoidosis].

Pituitary metastasis and sarcoidosis are two causes of pituitary stalk thickening. Their association has been described ago three decades. In this setting, we report a case of panhypopituitarism revealing pituitary metastasis from a small-cell lung carcinoma associated with sarcoidosis. A 49 year-old smoking patient with type 2 diabetes was admitted for acute adrenal failure with polyuria polydipsia syndrome and a pituitary tumor syndrome. Hormone explorations confirmed anterior pituitary insufficiency. Water restriction revealed central diabetes insipidus. The hypothalamic-pituitary MRI revealed a 1-cm sellar mass with nodular thickening of the stalk. The chest radiograph showed a heterogeneous opacity in the left lung. The thoraco-abdominal scan demonstrated a mass in the left lung highly suggestive of malignancy and many enlarged mediastinal nodes, hepatic nodules, and hypertrophy of the left adrenal. Bronchoscopy was performed three times and showed infiltration of the left bronchial tree but histological examination of the bronchial biopsies was negative for all samples. Ultrasound-guided biopsy of the liver was achieved and histology demonstrated sarcoidosis. The diagnosis of sarcoidosis was incompatible with the deterioration of the patient's general status. Subsequent radiographic explorations showed an increase in the size of the tumor mass and histological evaluation of a scan-guided trans-thoracic biopsy demonstrated small-cell carcinoma. Small-cell lung carcinoma is the most common cancer with pituitary metastasis. The proposed link between sarcoidosis and malignancy has remained controversial but has not been proven false.

Adrenal Gland Diseases↗
PubMed2003

Calpain-mediated AQP2 proteolysis in inner medullary collecting duct.

Vitamin D-elicited hypercalcemia/hypercalciuria is associated with polyuria in humans and in animal models. In rats, dihydrotachysterol (DHT) induces AQP2 water channel downregulation despite unaltered AQP2 mRNA expression and thus we investigated the mechanism of AQP2 degradation. Incubation of AQP2-containing inner medullary collecting duct (IMCD) endosomes with Ca(2+) or calpain elicited AQP2 proteolysis, an effect abolished by leupeptin. This endogenous, Ca(2+)-sensitive protease activity exhibited a different proteolytic digest pattern from trypsin, which also degraded AQP2 in vitro. IMCDs contain abundant micro-calpain protein and functional calpain proteolytic activity as demonstrated by immunohistochemistry, immunoblotting, and gel zymography. Furthermore, by small particle flow cytometry we demonstrated that micro-calpain colocalizes with apical IMCD endosomes. DHT does not appear to elicit general proteolysis, however, in addition to AQP2 degradation, DHT treatment also diminished micro-calpain and calpastatin expression although whether these changes contributed to the AQP2 instability remains unclear. Together, these data show for the first time that AQP2 is a substrate for calpain-mediated proteolysis and that furthermore, micro-calpain, like AQP2, is both highly expressed in renal inner medulla and localized to apical IMCD endosomes.

Animals↗
PubMed1996

Characterization of endothelin receptors in streptozotocin-induced diabetic rat vas deferens.

As there is increasing evidence that diabetes induces changes in the plasma levels of endothelins (ETs) and in the properties of ET receptors in peripheral tissues, and as there are reports indicating the presence of significant amounts of ET receptors in mammalian vasa deferentia, we studied possible alterations in ET receptor characteristics in the vasa deferentia of the following groups of rats: 8 weeks diabetic (D8), 8 weeks age-matched control (C8), 16 weeks diabetic (D16), 16 weeks diabetic-insulin-treated (started 8 weeks after the onset of diabetes) (DI16), and 16 weeks age-matched control (C16). Diabetes was induced by the i.v. injection of 65 mg/kg streptozotocin (STZ). Diabetic rats had hyperglycemia, hypoinsulinemia, glucosuria, polydipsia, and polyuria and had smaller vasa deferentia than control and diabetic-insulin-treated animals. Receptor binding experiments with [125I]ET-1 demonstrated that the densities of ET receptors in vasa deferentia from D8, C8, D16, DI16, and C16 animals were 377 +/- 11, 255 +/- 24, 315 +/- 18, 210 +/- 12, and 214 +/- 7 fmol/mg of protein, respectively. [125I]ET-1 binding to the ET receptors was inhibited by ET-1 (non-selective), BQ 610 (ETA selective), ET-3 (ETC selective), and IRL 1620 (ETB selective) with the following rank order of Ki values: ET-1 < BQ 610 < ET-3 < < IRL 1620. The pharmacological profile of the ET receptors was similar in all groups and was consistent with the predominance of the ETA receptor subtype in the rat vasa deferentia. Our data indicate that experimental diabetes up-regulates the density of ET receptors in the rat vasa deferentia and that the receptor up-regulation is reversed by insulin treatment.

Animals↗
PubMed1999

Hyperalgesic response to noxious stimulation in genetically polydipsic mice.

Inbred mice, STR/N, are known to exhibit extreme polydipsia and polyuria but no abnormality in the response to exogenous vasopressin (AVP) and renal functions. Our previous studies have revealed that the brain opioid system is involved in the polydipsia of these mice. We here report that the STR/N mice show a decrease in the nociceptive threshold and a low, anti-nociceptive sensitivity to opioid receptors agonists. The paw-withdrawal latency (PWL) on a hot-plate in the STR/N mice was significantly shorter than that in their controls (BALB/c and C3H mice). This hyperalgesia was not affected by water restriction. Subcutaneous (s.c.) injections of morphine (5 mg/kg) and a kappa-opioid receptor agonist, U50,488H (16 mg/kg) had no effect on the PWL in the STR/N mice, whereas the control mice prolonged PWL after administration of the opioids. However, the STR/N mice gained the ability to show morphine analgesia after up-regulation of the opioid system by repeated administration of naltrexone (s.c., 5 mg/kg) for 3 consecutive days. The results suggest that the anti-nociceptive function of the opioid system is down-regulated in STR/N mice as is observed in chronic morphine-treated animals.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗