scholarly journals Pharmacokinetics and Central Accumulation of Delta-9-Tetrahydrocannabinol (THC) and its Bioactive Metabolites are Influenced by Route of Administration and Sex

2021 ◽  
Author(s):  
Samantha L Baglot ◽  
Catherine Hume ◽  
Gavin N. Petrie ◽  
Robert J Aukema ◽  
Savannah HM Lightfoot ◽  
...  
Keyword(s):  
Animal Studies ◽  
Data Interpretation ◽  
Bioactive Metabolites ◽  
Blood Levels ◽  
Administration Route ◽  
Sprague Dawley ◽  
North Americans ◽  
Sprague Dawley Rats ◽  
Cannabis Consumption ◽  
Over Time

Up to a third of North Americans over 16 years old report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human cannabis consumption are critical to study its impacts on brain and behaviour. Nevertheless, most animal studies to date examine effects of cannabis through injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics of each administration route. The current study directly examined if administration route (injection versus inhalation), with dosing being matched on peak THC blood levels, alters the metabolism of THC, and the central accumulation of THC and its metabolites over time. Adult male and female Sprague-Dawley rats received either a single intraperitoneal injection of THC (2.5 mg/kg) or a single (15 min) session of inhaled exposure to THC distillate (100 mg/mL) vapour. Blood and brains were collected at 15, 30, 60, 90 and 240 minutes post-exposure for analysis of THC and metabolites through mass spectrometry-liquid chromatography. Inhalation results in immediate hypothermia, whereas injection results in delayed hypothermia. Despite achieving comparable peak concentrations of blood THC in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentrations, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence that THC and its metabolites exhibit different pharmacokinetic profiles following inhalation versus injection, which could have significant impacts for data interpretation and generalizability. Accordingly, we suggest that translational work in the realm of THC and cannabis strongly consider using inhalation models over those that employ injection.

scholarly journals Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samantha L. Baglot ◽  
Catherine Hume ◽  
Gavin N. Petrie ◽  
Robert J. Aukema ◽  
Savannah H. M. Lightfoot ◽  
...  
Keyword(s):  
Animal Studies ◽  
Data Interpretation ◽  
Bioactive Metabolites ◽  
Human Consumption ◽  
Administration Route ◽  
Sprague Dawley ◽  
North Americans ◽  
Sprague Dawley Rats ◽  
The Impact ◽  
Over Time

AbstractUp to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study

1996 ◽  
Vol 271 (6) ◽  
pp. H2246-H2253 ◽  
Author(s):  
S. Tjen-A-Looi ◽  
R. Ekman ◽  
J. Osborn ◽  
I. Keith
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressure Effects ◽  
Blood Levels ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Calcitonin Gene ◽  
Eta Receptor ◽  
Pulmonary Arterial

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

scholarly journals Pulmonary Toxicity, Distribution, and Clearance of Intratracheally Instilled Silicon Nanowires in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Jenny R. Roberts ◽  
Robert R. Mercer ◽  
Rebecca S. Chapman ◽  
Guy M. Cohen ◽  
Sarunya Bangsaruntip ◽  
...  
Keyword(s):  
Silicon Nanowires ◽  
Pulmonary Toxicity ◽  
Lung Damage ◽  
Collagen Deposition ◽  
Wire Length ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Dose Dependent ◽  
Over Time

Silicon nanowires (Si NWs) are being manufactured for use as sensors and transistors for circuit applications. The goal was to assess pulmonary toxicity and fate of Si NW using anin vivoexperimental model. Male Sprague-Dawley rats were intratracheally instilled with 10, 25, 50, 100, or 250 μg of Si NW (~20–30 nm diameter; ~2–15 μm length). Lung damage and the pulmonary distribution and clearance of Si NW were assessed at 1, 3, 7, 28, and 91 days after-treatment. Si NW treatment resulted in dose-dependent increases in lung injury and inflammation that resolved over time. At day 91 after treatment with the highest doses, lung collagen was increased. Approximately 70% of deposited Si NW was cleared by 28 days with most of the Si NW localized exclusively in macrophages. In conclusion, Si NW induced transient lung toxicity which may be associated with an early rapid particle clearance; however, persistence of Si NW over time related to dose or wire length may lead to increased collagen deposition in the lung.

Effect of circulating vasopressin on arterial pressure regulation in rats

1989 ◽  
Vol 257 (1) ◽  
pp. H209-H218 ◽  
Author(s):  
C. M. Pawloski ◽  
N. M. Eicker ◽  
L. M. Ball ◽  
M. L. Mangiapane ◽  
G. D. Fink
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Body Fluid ◽  
Area Postrema ◽  
Sodium Intake ◽  
Blood Levels ◽  
Fluid Composition ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Autonomic Cardiovascular Control

It has been hypothesized that moderately increased blood levels of arginine vasopressin (AVP) contribute to the development and/or maintenance of hypertension. In this study, male Sprague-Dawley rats on a fixed 1 meq daily sodium intake received 10-day intravenous infusions of 0.2 and 2.0 ng.kg-1.min-1 AVP. The higher infusion rate was above the acute vasoconstrictor threshold for AVP administration and also produced a maximal antidiuretic effect. During chronic AVP administration, however, daily mean arterial pressure, heart rate, and body fluid composition were not changed, despite a maintained antidiuresis. To test the hypothesis that circulating AVP failed to cause hypertension as a result of sensitization of the baroreflex or a direct sympathoinhibitory effect of the peptide, additional experiments were performed in rats subjected to sinoaortic denervation (SAD) or ablation of the area postrema (APX). Infusion of AVP for 10 days into SAD or APX rats caused a sustained antidiuresis but did not change arterial pressure, heart rate, or body fluid composition. In all groups of rats, the depressor response to ganglionic blockade (20 mg/kg hexamethonium) was used to estimate the autonomic component of resting arterial pressure; no change in autonomic cardiovascular control was found using this method in any of the groups during AVP infusion. Long-term elevation of plasma AVP in rats, therefore, does not cause hypertension or significantly affect autonomic regulation of arterial pressure.

Abstract 149: Zoniporide Combined with α-Methylnorepinephrine Promotes Greater Hemodynamic Stability than Either Agent Alone During Chest Compression in Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lorissa Lamoureux ◽  
Herbert K Whitehouse ◽  
Jeejabai Radhakrishnan ◽  
Raúl J Gazmuri
Keyword(s):  
Chest Compression ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Blood Flows ◽  
Compression Time ◽  
Sprague Dawley Rats ◽  
Sodium Hydrogen Exchanger ◽  
Ventricular Distensibility ◽  
Over Time

Background: We have reported in animal models of cardiac arrest that sodium hydrogen exchanger-1 (NHE-1) inhibition - by attenuating reperfusion injury - helps preserve left ventricular distensibility yielding higher forward blood flows during chest compression. Others have reported that α-methylnorepinephrine (α-MNE) - a selective peripheral α2-adrenoreceptor agonist - is superior to epinephrine given its lack of β-agonist effect that intensifies myocardial ischemia. We examined in a rat model of VF the effects of combining the NHE-1 inhibitor zoniporide (ZNP) with α-MNE during CPR, expecting to elicit a vasopressor effect (α-MNE) that is better maintained over time because of ZNP. Methods: VF was electrically induced in 32 male retired breeder Sprague-Dawley rats and left untreated for 8 minutes. Chest compression was then initiated, gradually increasing the depth of compression (maximum 17 mm) to attain an aortic diastolic pressure of 28 mmHg by the end of minute 2, maintaining such level for the remaining 6 minutes of chest compression, time at which defibrillation was attempted. The rats were randomized 1:1:1:1 to receive a 3 mg/kg bolus of ZNP or 0.9% NaCl before starting chest compression and a 100 μg/kg bolus of α-MNE or its vehicle at minute 2 of chest compression with the investigators blind to the assignment. Results: The ratio between the aortic diastolic pressure and depth of compression (Figure) was higher - as expected - in rats that received α-MNE(+) given its vasopressor effect. The effect, however, was not maintained and declined over time; but to a significantly lesser degree in rats that also received ZNP; i.e., α-MNE(+)/ZNP(+) group. Conclusions: The findings support a favorable interaction between α-MNE and ZNP; the first prompting needed peripheral vasoconstriction - likely with less concomitant myocardial injury - and the latter preserving left ventricular distensibility, which combined enhance the hemodynamic efficacy of chest compression.

Proper Choice of Vessels for Supermicrosurgery Training: An Experimental Animal study

2018 ◽  
Vol 34 (09) ◽  
pp. 742-748
Author(s):  
Yooseok Ha ◽  
Seung Song ◽  
Nak Kang ◽  
Sang-Ha Oh
Keyword(s):  
Experimental Animal ◽  
Animal Studies ◽  
Free Flaps ◽  
Vessel Diameter ◽  
Sprague Dawley ◽  
Epigastric Vessel ◽  
Sprague Dawley Rats ◽  
Pedicle Length ◽  
Experimental Animal Study ◽  
Arteries And Veins

Background Reconstruction using supermicrosurgery, a technique of microneurovascular anastomosis for smaller vessels (< 0.8 mm), has become popular. Experimental animal studies for supermicrosurgery training have been reported; however, there have been few studies performed according to vessel diameter and pedicle length. In this study, the external diameters of four vessels (femoral, superficial epigastric, axillary, and common thoracic) and pedicle length of two flaps (superficial epigastric and common thoracic–long thoracic) were measured. Methods The inguinal and pectoral regions of Sprague-Dawley rats (n = 19) were dissected anatomically, and the external diameters of the four vessels were measured (right and left, artery and vein measured separately). After elevating the superficial epigastric and common thoracic–long thoracic flaps, the pedicle length of the flaps was also measured. Results Among the 16 vessels examined, the external diameters of 11 and 5 vessels were above and below 0.8 mm, respectively. The external diameters of the superficial epigastric vessel and common thoracic vessel (both arteries and veins) were below 0.8 mm. The external diameters of the femoral and axillary vessels (veins) were above 0.8 mm. The length of the common thoracic–long thoracic pedicle was approximately10 mm longer than that of the superficial epigastric pedicle. Conclusions The external diameters of the superficial epigastric vessel and common thoracic vessel are small enough for supermicrosurgery training. The pedicle lengths of both the superficial epigastric and common thoracic–long thoracic flaps are sufficient to perform free flap experiments. Supermicrosurgical free flaps using these two vessels and a study of the physiology and pharmacology of the flaps will likely be possible in the future.

scholarly journals 2,4,6-Tribromophenol Disposition and Kinetics in Pregnant and Nursing Sprague Dawley Rats

2020 ◽  
Vol 178 (1) ◽  
pp. 36-43
Author(s):  
Gabriel A Knudsen ◽  
Margaret Chapman ◽  
Andrew W Trexler ◽  
Christopher T Juberg ◽  
Linda S Birnbaum
Keyword(s):  
Breast Milk ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Stomach Contents ◽  
Human Breast Milk ◽  
Human Breast ◽  
Sprague Dawley ◽  
Environmental Matrices ◽  
Sprague Dawley Rats ◽  
Over Time

Abstract 2,4,6-Tribromophenol (TBP, CAS no. 118-79-6) is a brominated chemical used as a precursor, flame retardant, and wood antifungal agent. TBP is detected in environmental matrices and biota, including human breast milk, placenta, and serum. To address reports of TBP accumulation in human placenta and breast milk, studies were conducted to characterize TBP disposition and toxicokinetics in timed-pregnant or nursing Sprague Dawley rats following a single oral dose to the dam. Animals were administered [14C]-TBP (10 μmol/kg, 25 µCi/kg, 4 ml/kg) by gavage on gestation day 12 and 20, or postnatal day 12 and serially euthanized between 15 min and 24 h for collection of blood and tissues from the dam and fetuses/pups. Observed plasma TBP Cmax (3 and 7 nmol/ml) occurred at 15 min in both GD12 and GD20 dams while Cmax (3 nmol/ml) was observed at 30 min for PND12 dams. Concentrations in tissues followed plasma concentrations, with kidneys containing the highest concentrations at 30 min. GD12 litters contained a sustained 0.2%–0.3% of the dose (5–9 nmol/litter) between 15 min and 6 h while GD20 fetuses (2%–3%) and placentas (0.3%–0.5%) had sustained levels between 30 min and 12 h. The stomach contents (approx. 1 nmol-eq/g, 6–12 h), livers (0.04–0.1 nmol-eq/g) and kidneys (0.1–0.2 nmol-eq/g) of PND12 pups increased over time, indicating sustained exposure via milk. Systemic exposure to TBP and its metabolites occurs in both the directly exposed mother and the indirectly exposed offspring and is rapid and persistent after a single dose in pregnant and nursing rats.

scholarly journals Validation of an efficient and continuous urodynamic monitoring system for awake, unrestrained, chronic rodent studies

2020 ◽  
Vol 318 (1) ◽  
pp. F86-F95
Author(s):  
D. Angoli ◽  
A. Geramipour ◽  
Z. C. Danziger
Keyword(s):  
Animal Studies ◽  
Measurement Problem ◽  
Automatic Monitoring ◽  
Bladder Volume ◽  
Bladder Function ◽  
Light Cycle ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Healthy Female ◽  
Surgical Recovery

The postvoid residual (PVR) is an important measure of bladder function, but obtaining PVR is burdensome because bladder volume must be measured at the time of voiding. The PVR measurement problem has led to experimental tricks in animal studies (infusing the bladder at supraphysiological rates and limiting animal observation windows) to keep the number of observed voids statistically robust while reducing the time an experimenter must be present. Our solution to the PVR measurement problem is a system called Automatic Monitoring for Efficient, Awake, Sensitive, Urine Residual Estimation (AMEASURE). AMEASURE combines metabolic cages and optimization algorithms to estimate continuously PVR for every voiding event 24 h/day for multiple weeks, without artificial bladder infusion, continuous experimenter supervision, anesthesia, or restraints. Using AMEASURE, we obtained voided volumes, PVRs, and other urodynamic parameters continuously for 21 days in 10 healthy female Sprague-Dawley rats. Importantly, this required only one manual measurement of animals’ bladder volume every 12 h. We validated the accuracy of the system experimentally and in simulation. We detected marked differences in voiding frequency and efficiency between light and dark cycles and found that voiding frequency increased over time during the dark cycle (but not the light cycle), due to surgical recovery, cage acclimation, and socialization. This tool enhances the relevance of rodent models to the study of human lower urinary tract by expanding observation periods and obviating the need to infuse the bladder and facilitates the study of conditions for which behavioral, social, or circadian factors play essential roles.

ANG II-induced downregulation of RBF after a prolonged reduction of renal perfusion pressure is due to pre- and postglomerular constriction

2004 ◽  
Vol 286 (5) ◽  
pp. R865-R873 ◽  
Author(s):  
Charlotte Mehlin Sorensen ◽  
Paul Peter Leyssac ◽  
Max Salomonsson ◽  
Ole Skott ◽  
Niels-Henrik Holstein-Rathlou
Keyword(s):  
Perfusion Pressure ◽  
Plasma Renin ◽  
Renal Perfusion ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Renal Perfusion Pressure ◽  
Sprague Dawley Rats ◽  
Proximal Tubular ◽  
Tubular Flow ◽  
Over Time

Previous experiments from our laboratory showed that longer-lasting reductions in renal perfusion pressure (RPP) are associated with a gradual decrease in renal blood flow (RBF) that can be abolished by clamping plasma ANG II concentration ([ANG II]). The aim of the present study was to investigate the mechanisms behind the RBF downregulation in halothane-anesthetized Sprague-Dawley rats during a 30-min reduction in RPP to 88 mmHg. During the 30 min of reduced RPP we also measured glomerular filtration rate (GFR), proximal tubular pressure (Pprox), and proximal tubular flow rate (QLP). Early distal tubular fluid conductivity was measured as an estimate of early distal [NaCl] ([NaCl]ED), and changes in plasma renin concentration (PRC) over time were measured. During 30 min of reduced RPP, RBF decreased gradually from 6.5 ± 0.3 to 6.0 ± 0.3 ml/min after 5 min (NS) to 5.2 ± 0.2 ml/min after 30 min ( P < 0.05). This decrease occurred in parallel with a gradual increase in PRC from 38.2 ± 11.0 × 10-5 to 87.1 ± 25.1 × 10-5 Goldblatt units (GU)/ml after 5 min ( P < 0.05) to 158.5 ± 42.9 × 10-5 GU/ml after 30 min ( P < 0.01). GFR, Pprox, and [NaCl]ED all decreased significantly after 5 min and remained low. Estimates of pre- and postglomerular resistances showed that the autoregulatory mechanisms initially dilated preglomerular vessels to maintain RBF and GFR. However, after 30 min of reduced RPP, both pre- and postglomerular resistance had increased. We conclude that the decrease in RBF over time is caused by increases in both pre- and postglomerular resistance due to rising plasma renin and ANG II concentrations.

Diabetes in pregnancy: influence of genetic background and maternal diabetic state on the incidence of skeletal malformations in the fetal rat

1986 ◽  
Vol 113 (3_Suppl) ◽  
pp. S66-S73 ◽  
Author(s):  
Ulf J. Eriksson ◽  
V. Elisabeth Dahlström ◽  
Hans O. Lithell
Keyword(s):  
Female Rats ◽  
Blood Levels ◽  
Suitable Model ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Diabetic State ◽  
Skeletal Malformations ◽  
Sprague Dawley Rats ◽  
Fetal Rat ◽  
Rat Strain

Abstract. Female Sprague-Dawley rats from two different substrains (denoted U and H rats) were made manifest diabetic (MD) with a single iv injection of streptozotocin 2–4 weeks before mating. In some MD animals insulin treatment was started 1–3 weeks before mating (denoted MDI rats) and in a majority of these animals the treatment was interrupted during two days of pregnancy, i.e. gestational days 2 + 3, 4 + 5, 6 + 7, 8 + 9 or 10 + 11. The pregnant rats were killed on gestational day 20. The offspring of MD and MDI rats of the U substrain showed skeletal malformations (micrognathia and sacral dysgenesis) at a rate up to 19%, whereas the MD and MDI fetuses of the H strain did not display any skeletal malformations. Offspring of the U strain with sacral dysgenesis exhibited lack of a tail and no staining of osseous and cartilagenous tissue in the sacral-caudal region, suggesting total absence of vertebrae. The offspring of the dibetic U rats tended to be more readily resorbed, were smaller and tended to have slightly larger placentae than those of the diabetic H rats. The severity of the diabetic state in pregnant and nonpregnant female rats – as reflected by body and kidney weights, blood levels of HbA1c, carbohydrate and lipid metabolites – did not differ significantly between the U and H rats. These results are in concert with the notion that congenital malformations result from a teratogenic insult in a genetically predisposed organism. The described malformation-prone rat strain (U) may be a suitable model for the future elucidation of teratological mechanisms in diabetic pregnancy.

Sign in / Sign up

Export Citation Format

Share Document