PubMed Health⌕ Search

Biomedical subjects

R G Pertwee

Publications and source records attributed to R G Pertwee.

90 records · Page 5Linked to original sources
PubMed1986

Effects of subanesthetic doses of inert gases on behavioral thermoregulation in mice.

Mice exposed to subanesthetic partial pressures of N2O (0.25 to 0.75 atm) or N2 (5.7 or 11.33 atm) and allowed to choose between a warm and a cool environment showed a marked preference for the cooler environment. This behavior was associated with the onset of hypothermia, with deep body temperature falling by up to about 3 degrees C, usually to a new, steady level. Both the length of time spent in the cooler environment and the degree of the hypothermia produced increased with the partial pressure of N2O or N2 used. The effects of N2O on behavioral thermoregulation and body temperature were reversible. There was a correlation between anesthetic potency and the ability of both gases to alter thermoregulation, suggesting that the effect of these agents on thermoregulation was caused by the same molecular interactions as those which underlie anesthesia. Since both gases elicited changes in behavioral thermoregulation promoting rather than opposing the onset of hypothermia, it is concluded that they may have acted to lower the level at which deep body temperature was being regulated.

Anesthetics↗
PubMed1982

Changes in body temperature and oxygen consumption rate of conscious mice produced by intrahypothalamic and intracerebroventricular injections of delta 9-tetrahydrocannabinol.

delta 9-Tetrahydrocannabinol (delta 9-THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured. At an ambient temperature of 22 degrees C, injections of delta 9-THC into the fourth ventricle (5 and 10 microgram) produced dose-dependent falls in rectal temperature. Hypothermia was also observed after injections of the drug into the hypothalamus (5 and 10 microgram) or into the third ventricle (10 microgram). The hypothermia produced by delta 9-THC was associated with a fall in oxygen consumption rate. Falls in rectal temperature and in oxygen consumption rate were significantly greater after injection of delta 9-THC than after injection of the drug vehicle, Tween 80. The falls in rectal temperature and oxygen consumption rate produced by injection of delta 9-THC into the fourth ventricle were abolished by elevation of the ambient temperature from 22 to 32 degrees C. A pretreatment that consisted of subcutaneous injections of delta 9-THC (20 mg/kg) given once daily for three days produced tolerance to the hypothermic effect of the drug when injected on day 4 either into the fourth ventricle (10 microgram) or into a lateral tail vein (2.0 mg/kg). The results suggest that delta 9-THC acts centrally to alter thermoregulation in mice not only when it is injected directly into the hypothalamus or cerebral ventricles but also when it is given intravenously. After intraventricular or intravenous administration the drug may act at extrahypothalamic as well as at hypothalamic sites. The data also support the hypothesis that in mice, tolerance to the hypothermic effect of A9-THC is pharmacodynamic and does not depend on changes in metabolism or distribution of the drug.

Animals↗
PubMed1980

Thermoregulatory effects of N6-2'-Q-dibutyryl adenosine 3',5'-monophosphate in the restrained mouse.

1 The N6-2-O-dibutyryl derivative of adenosine 3',5'-monophosphate (db cyclic AMP) has been micro-injected into the third cerebral ventricle of the unanaesthetized, restrained mouse and the effects on body temperature and thermoregulatory activities observed. 2 Db cyclic AMP (4, 16 and 32 micrograms) injected intracerebroventricularly produced hypothermia when compared with temperature responses to sodium n-butyrate (6.8 micrograms). 3 Hypothermia induced by db cyclic AMP in mice was associated with a fall in oxygen consumption together with behavioural and autonomic heat loss activities but not cutaneous vasodilatation. The effects on rectal temperature and oxygen consumption were dose-dependent. 4 The falls in rectal temperature and oxygen consumption induced by db cyclic AMP (4 micrograms) were decreased by elevation of the environmental temperature from 22 to 32 degrees C and abolished at 36 degrees C. 5 It is concluded db cyclic AMP may inhibit central events mediating the rise in metabolic heat production in mice upon exposure to cold environments.

Animals↗
PubMed1979

Effects of delta 9-tetrahydrocannabinol, 2.4-dinitrophenol and pentolinium tartrate on behavioural thermoregulation in mice.

1 A new apparatus in which mice are allowed to shuttle between the warm and cool parts of a continuous oval tunnel has been designed for the measurement of drug effects on behavioural thermoregulation.2 The length of time that untreated mice spent in the warmer part of the apparatus (tunnel wall temperature 38 degrees C) was found to be inversely related to the temperature of the cooler part (wall temperature 18 degrees , 24 degrees or 30 degrees C).3 Mice treated with 2,4-dinitrophenol at a dose known to be hyperthermic at an ambient temperature of 32 degrees C (20 mg/kg s.c.) spent an increased length of time in the cooler part of the apparatus (wall temperature 18 degrees C) and did not exhibit any change in rectal temperature.4 Mice treated with pentolinium tartrate at a dose known to be hypothermic at room temperature (5.0 mg/kg i.v.) spent a decreased length of time in the cooler part of the apparatus (wall temperature 24 degrees C) and did not exhibit any change in rectal temperature.5 It is concluded from the above results that the apparatus can be used to measure drug effects on behavioural thermoregulation.6 In experiments of 30 min duration, mice treated with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) at doses known to be hypothermic and to lower oxygen consumption at room temperature (20 mg/kg i.p. or 2.0 mg/kg i.v.) spent a longer time in the warmer part of the apparatus between 15 and 30 min after injection. Rectal temperatures measured 30 min after injection were only slightly less than those of control mice. In these experiments the wall temperature of the cool tunnel was 24 degrees C.7 In experiments of 15 min duration, mice treated with Delta(9)-THC (20 mg/kg) and then placed in the apparatus spent more time in the cooler part of the apparatus (wall temperature 24 degrees C) and exhibited a large fall in rectal temperature.8 It is concluded that immediately after injection of Delta(9)-THC the mice do not attempt to oppose drug-induced falls in deep body temperature by moving into a warm environment and that only later do the animals demonstrate a preference for a warm environment.

Animals↗
PubMed1977

Effects of delta9-tetrahydrocannabinol on the rates of oxygen consumption of mice.

1. Experiments with untreated mice confirmed that at ambient temperatures below 30 degrees C, the oxygen consumption rate of mice normally kept at about 23 degrees C varies inversely with ambient temperature. 2. At given ambient temperatures in the range 20 to 31 degrees C the oxygen consumption rate was 32 to 43% greater for restrained than for unrestrained mice. 3. Hypothermia induced in restrained mice by delta9-tetrahydrocannabinol (delta9-THC) (1.0 to 4.0 mg/kg i.v.) was accompanied by marked falls in the rate of oxygen consumption. The size of these falls parallelled the degree of hypothermia and increased both with increases in dose and with decreases in the ambient temperature. The oxygen consumption rates of unrestrained mice were also lowered by hypothermic doses (10 to 40 mg/kg i.p.) of delta9-THC. 4. The maximum falls in oxygen consumption rate occurred at earlier times after drug administration than the maximum falls in rectal temperature. 5. At none of the ambient temperatures studied did the oxygen consumption rates of delta9-THC-treated mice fall significantly below the basal levels (59 +/- 3 ml 25 g-1 h-1) of unrestrained, resting mice at 30 degrees C. 6. The hypothesis that reduced rates of heat production contribute significantly towards the hypothermia induced by delta9-THC in our experiments is discussed. The possibility that biological processes responsible for increased heat production in response to cold are more sensitive to delta9-THC than those processes governing basal rates of heat production at thermally neutral environmental temperature is also raised.

Animals↗
PubMed1977

Effects of delta9-tetrahydrocannabinol and cannabidiol on a Mg2+-ATPase of synaptic vesicles prepared from rat cerebral cortex.

1. delta9-Tetrahydrocannabinol and cannabidiol both exhibited a concentration-related inhibition of Mg2+-ATPase of vesicles prepared from synaptosomes isolated from rat cerebral cortex. Cannabidiol was about 3 times more potent than tetrahydrocannabinol. 2. These results were similar to those obtained previously using drugs with well established anticonvulsant activity. 3. Tetrahydrocannabinol at a sub-inhibitory concentration (1 micronM) increased the activity of the Mg2+-ATPase relative to values obtained with vehicle controls.

Adenosine Triphosphatases↗
PubMed1974

Tolerance to the effect of delta1-tetrahydrocannabinol on corticosterone levels in mouse plasma produced by repeated administration of cannabis extract or delta1-tetrahydrocannabinol.

1 Three injections of cannabis extract (500 mg/kg s.c. given over 3 or 5 days) diminished thymus gland weight but not the weights of spleen or liver in weanling female and adult male mice kept at room temperature.2 Both cannabis extract (500 mg/kg s.c.) and Delta(1)-tetrahydrocannabinol (Delta(1)-THC; 10 and 20 mg/kg i.p.) elevated corticosterone levels in mouse plasma.3 A pretreatment that consisted of three daily subcutaneous injections of 500 mg/kg of cannabis extract and that was shown to produce tolerance to the ;cataleptic' effect of Delta(1)-THC (2 mg/kg i.v.) in mice, also produced tolerance to the effect of Delta(1)-THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma. However, this pretreatment did not reduce the rise in plasma corticosterone concentration produced by immobilization.4 Tolerance to the effect of Delta(1)-THC (10 mg/kg i.p.) on corticosterone levels in mouse plasma was also produced by the pretreatment of mice with a single injection of Delta(1)-THC (10 mg/kg s.c.). Three daily injections of Delta(1)-THC (10 or 30 mg/kg s.c.) also produced tolerance.5 In a thermoneutral environment (30-32 degrees C) in which cannabis extract does not produce hypothermia, the drug no longer reduced thymus gland weight. However the effect of cannabis extract and of Delta(1)-THC on corticosterone plasma levels was the same at room temperature as at 30-32 degrees C. Tolerance to the latter effect of Delta(1)-THC was also produced equally readily under the two conditions.6 It is concluded that pretreatment with cannabis extract or Delta(1)-THC can produce tolerance to the effect of Delta(1)-THC on corticosterone levels in mouse plasma and does so without impairing the effect of immobilization stress on corticosterone release. In addition, both the rise in corticosterone plasma levels produced by cannabis or Delta(1)-THC and the development of tolerance to this effect can still take place in the absence of hypothermia.

Animals↗
PubMed1973

Brain levels of delta1-tetrahydrocannabinol and its metabolites in mice tolerant to the hypothermic effect of delta1-tetrahydrocannabinol.

Repeated voluntary consumption of cannabis in milk (approximately 8 mg per day for 15 days) produced in mice tolerance to the hypothermic effect of tritiated Delta(1)-tetrahydrocannabinol ([(3)H]-Delta(1)-THC; 2 mg/kg i.v.) but not to the effect of [(3)H]-Delta(1)-THC on immobility index. The development of tolerance was not accompanied by any detectable change in levels of radioactivity in the brain assigned to Delta(1)-THC or its metabolites. It was concluded that changes in metabolism or distribution of Delta(1)-THC are not responsible for tolerance at least to the hypothermic effect of Delta(1)-THC in mice.

Animals↗
PubMed1972

The ring test: a quantitative method for assessing the 'cataleptic' effect of cannabis in mice.

1. A bioassay for cannabis, called the ring test, has been developed in which the percentage of the total time spent on a horizontal wire ring during which a mouse remains completely immobile is recorded.2. The effect of cannabis on mobility is a dose-related, graded response.3. Threshold doses of cannabis extract are 12.5 mg/kg when injected intravenously, and 100 mg/kg when injected intraperitoneally or subcutaneously.4. The method provides a measure of the ;cataleptic' effect of cannabis. Chlorpromazine in doses of 1 mg/kg upwards also produces the effect but barbitone does not.5. It is concluded that Delta(1)-tetrahydrocannabinol (Delta(1)-THC) is largely responsible for the effect of cannabis extract on mobility; the potency ratio of Delta(1)-THC to cannabis extract is between 10 and 20. Delta(1)-Tetrahydrocannabidivarol (Delta(1)-THD) also affects mobility but is less active than Delta(1)-THC. Cannabidiol has no effect when injected intraperitoneally in doses up to 100 mg/kg.

Animals↗
PubMed1972

A metabolic interaction in vivo between cannabidiol and 1 -tetrahydrocannabinol.

The effect of pretreatment with cannabidiol (CBD; 50 mg/kg i.p.) on the distribution of radioactivity in chromatograms of ethyl acetate extracts of the brains of mice injected with tritiated Delta(1)-tetrahydrocannabinol ((3)H-Delta(1)-THC; 1.0 mg/kg i.v.) was determined. The pretreatment with CBD produced significant increases in the levels of radioactivity in the brain assigned to Delta(1)-THC and its centrally active metabolite 7-hydroxy-Delta(1)-THC: the changes produced were respectively 1.4 and 2.0 fold.Pretreatment with CBD did not bring about any detectable change in the degree of 'catalepsy' produced by Delta(1)-THC. This negative finding may have been due to the wide limits of error that were obtained in the bioassay.

Animals↗
PubMed1972

Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism.

1. Cannabis extract prolonged sleeping time in mice in a thermally neutral environment (30-32 degrees C) in which hypothermia does not occur. The prolongation was dose related, just detectable at 50 mg/kg, and 4-fold at 500 mg/kg.2. Under these conditions, ether sleeping time was not prolonged.3. Cannabis extract inhibited the aerobic metabolism of phenazone by a microsome-rich 9,000 g supernatant of mouse liver homogenate capable of nicotinamide adenine dinucleotide phosphate (NADPH) generation.4. Delta(1)-Tetrahydrocannabinol (Delta(1)-THC) prolonged pentobarbitone sleep and inhibited phenazone metabolism, but its action was limited, and could not account for the effect of the extract. The carotenes and water-soluble fractions of the extract were inactive on pentobarbitone sleep.5. Cannabidiol was strongly active by both tests; in vivo 39.8 muM/kg (12.5 mg/kg) prolonged sleep by 190%, and in vitro 12.7 muM inhibited phenazone metabolism 20%. These actions were dose related, and could account for the effect of the extract.6. The prolongation of pentobarbitone sleep by cannabis extract in a dose of 200 mg/kg, intraperitoneally, was maximal when given 30 min before the pentobarbitone, still present at 3 h, but undetectable at 24 hours. No phase of enhanced metabolism at 24 or 48 h after single cannabis injection was detected.7. It is concluded that cannabis extract inhibits microsomal activity of mouse liver, chiefly by virtue of its cannabidiol content. It is probable that cannabis consumption by man could lead to altered disposal of many other drugs, used in medicine or otherwise.

Aerobiosis↗
PubMedDate not supplied

Enhancement of the hypothermic response of mice to delta-9-tetrahydrocannabinol by subhypothermic doses of chlorpromazine and phentolamine.

Pretreatment with subhypothermic doses of chlorpromazine, given directly into the IIIrd cerebral ventricle via a chronically implanted cannula (50 micrograms) or subcutaneously (0.75 mg/kg), was found to enhance the hypothermic response to delta-9-tetrahydrocannabinol (THC: 5 20 mg/kg i.p.) in unrestrained adult male MF1 mice, kept at 22 degrees C. Subcutaneous pretreatment with a subhypothermic dose of phentolamine (30 mg/kg) had a similar effect, whereas pretreatment with desipramine (10 mg/kg s.c.), mepyramine (2.3 and 11.5 mg/kg s.c.), methysergide (2 mg/kg s.c.), pimozide (1 and 5 mg/kg s.c.) or lignocaine (50 mg/kg s.c.), had no effect. Intracerebroventricular pretreatment with phentolamine was also without effect and it is concluded that this drug interacts with THC at some site located outside the brain. Since, in mg/kg terms, chlorpromazine was more potent in enhancing THC-induced hypothermia when given subcutaneously than when injected into the IIIrd ventricle, it too may interact with THC at a peripheral site. Indeed, chlorpromazine and phentolamine may both increase the hypothermic response to THC by antagonizing alpha-adrenoceptors on cutaneous blood vessels, thereby decreasing the capacity of animals to minimise peripheral blood flow by vasoconstriction. Alternatively, since the distribution of chlorpromazine within the brain may well have been less efficient after intraventricular than after subcutaneous injection, the possibility remains that chlorpromazine interacted centrally with THC.

Animals↗
PubMedDate not supplied

Cannabinoid receptors and their ligands.

There are at least two types of cannabinoid receptors, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors exist primarily on central and peripheral neurons, one of their functions being to modulate neurotransmitter release. CB(2) receptors are present mainly on immune cells. Their roles are proving more difficult to establish but seem to include the modulation of cytokine release. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether. Other endocannabinoids and cannabinoid receptor types may also exist. Although anandamide can act through CB(1) and CB(2) receptors, it is also a vanilloid receptor agonist and some of its metabolites may possess yet other important modes of action. The discovery of the system of cannabinoid receptors and endocannabinoids that constitutes the "endocannabinoid system" has prompted the development of CB(1)- and CB(2)-selective agonists and antagonists/inverse agonists. CB(1)/CB(2) agonists are already used clinically, as anti-emetics or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer. Following their release onto cannabinoid receptors, endocannabinoids are removed from the extracellular space by membrane transport and then degraded by intracellular enzymic hydrolysis. Inhibitors of both these processes have been developed. Such inhibitors have therapeutic potential as animal data suggest that released endocannabinoids mediate reductions both in inflammatory pain and in the spasticity and tremor of multiple sclerosis. So too have CB(1) receptor antagonists, for example for the suppression of appetite and the management of cognitive dysfunction or schizophrenia.

Animals↗