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Biomedical subjects

E Fride

Publications and source records attributed to E Fride.

At least 19 recordsLinked to original sources
PubMed2001

Critical role of the endogenous cannabinoid system in mouse pup suckling and growth.

Delta9-tetrahydrocannabinol, the active principle in marijuana, is a cannabinoid receptor agonist. Both the crude drug and delta9-tetrahydrocannabinol have been used as appetite promoters. The endogenous cannabinoid, arachidonoyl ethanolamide (anandamide), likewise a cannabinoid receptor agonist, has been shown to have the same effect. In contrast, the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (SR141716A) reduces food intake. Here, we report that administration of SR141716A to newly born mouse pups (either a single administration on postnatal day 1, or daily for a week as of postnatal day 2) had a devastating effect on milk ingestion and growth. The first 24 h after birth appeared the most critical for the growth stunting effect of SR141716A. Death followed within 4-8 days. Co-administration of delta9-tetrahydrocannabinol almost fully reversed the effect of the antagonist in the week-long regimen. Co-administration of 2-arachidonoyl glycerol, an endocannabinoid, with 2-palmitoyl glycerol and 2-linoleoyl glycerol, which enhance 2-arachidonoyl glycerol potency, resulted in a significant delay in mortality rates caused by the antagonist. We conclude that the endocannabinoid system plays a vital role in milk suckling, and hence in growth and development during the early stages of mouse life.

Animals↗
PubMed2001

2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor.

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).

Animals↗
PubMed1999

HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.

Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)-transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

Analgesics↗
PubMed1998

Endocannabinoids.

The background knowledge leading to the isolation and identification of anandamide and 2-arachidonoyl glycerol, the principal endocannabinoids is described. The structure-activity relationships of these lipid derivatives are summarized. Selected biochemical and pharmacological topics in this field are discussed, the main ones being levels of endocannabinoids in unstimulated tissue and cells, biosynthesis, release and inactivation of endocannabinoids, the effects of 'entourage' compounds on the activities of anandamide and 2-arachidonoyl glycerol, their signaling mechanisms and effects in animals.

Animals↗
PubMed1998

An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.

2-Arachidonoyl-glycerol (2-Ara-GI) has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-GI is accompanied by several 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2-Palm-Gl). These two esters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB1 or CB2; however, they significantly potentiate the apparent binding of 2-Ara-Gl and its apparent capacity to inhibit adenylyl cyclase. Together these esters also significantly potentiate 2-Ara-Gl inhibition of motor behavior, immobility on a ring, analgesia on a hot plate and hypothermia caused by 2-Ara-Gl in mice. 2-Lino-Gl, but not 2-Palm-GI, significantly inhibits the inactivation of 2-Ara-Gl by neuronal and basophilic cells. These data indicate that the biological activity of 2-Ara-Gl can be increased by related, endogenous 2-acyl-glycerols, which alone show no significant activity in any of the tests employed. This effect ('entourage effect') may represent a novel route for molecular regulation of endogenous cannabinoid activity.

Adenylyl Cyclase Inhibitors↗
PubMed1998

Biphasic effects of anandamide.

Effects of the endogenous cannabimimetic anandamide were assessed over a wide dose range in a series of physiological and behavioral assays. These included the tetrad of tests in mice commonly used to assess cannabinoid-induced effects (motor activity, ring catalepsy, hypothermia, and analgesia tests), as well as a model for agonistic behavior on dyadic interactions of singly housed males with nonaggressive group-housed partners. Anandamide-induced effects on leukocyte phagocytosis were measured in a chemiluminescence assay. Results indicated that the higher doses tested (10-100 mg/kg) produced the well-known inhibitory effects in all of the above parameters as well as inhibition of phagocytosis. The lowest dose of anandamide tested (0.01 mg/kg) stimulated behavioral activities in the open field, on the ring and aggressive behavior in timid singly housed mice. This dose of 0.01 mg/kg, also stimulated phagocytosis. We suggest several possible mechanisms to explain these findings such as a differential involvement of a Gs and a Gi protein activated at low and high doses, respectively, allosteric modulation of the cannabinoid, and activation of presynaptic cannabinoid receptors by low doses of anandamide.

Aggression↗
PubMed1996

Ontogenetic development of the response to anandamide and delta 9-tetrahydrocannabinol in mice.

We studied the ontogenetic response to cannabinoid receptor ligands by measuring motor activity and analgesia in response to anandamide or delta 9-THC from day 6 of age. No response to anandamide was observed up to the age of weaning (day 23), while a nonsignificant response to delta 9-THC was observed starting between days 15 and 20. This is compatible with observations that children respond to the antiemetic effects of THC without psychotropic side effects.

Aging↗
PubMed1996

Developmental aspects of anandamide: ontogeny of response and prenatal exposure.

Recent breakthroughs in cannabinoid research, including the identification of two cannabinoid receptors (CB receptors) and a family of endogenous ligands, the anandamides, may shed new light on the sequelae of pre- and perinatal exposure to cannabinoid receptor ligands and enable the experimental manipulation of the endogenous ligand in the developing organism. In the present study we examined the behavioural response to anandamide (ANA) in developing mice from day 13 into adulthood. We observed that depression of ambulation in an open field and the analgetic response to ANA are not fully developed until adulthood. In a separate set of experiments, we administered five daily injections of ANA (SC, 20 mg/kg) during the last trimester of pregnancy. No effects on birth weight, litter size, sex ratio and eye opening were detected after maternal ANA treatment. Further, no effects on open field performance of the offspring were observed until 4 weeks of age. However, from 40 days of age, a number of differences between the prenatal ANA and control offspring were detected. Thus, the offspring from ANA-treated dams showed impaired responsiveness to a challenge with ANA or delta 0-THC expressed as a lack of immobility in the ring test for catalepsy, hypothermia and analgesia. On the other hand, without challenge, they exhibited a spontaneous decrease in open field activity, catalepsy, hypothermia and a hypoalgetic tendency. These data suggest that exposure to excessive amounts of ANA during gestation alters the functioning of the ANA-CB receptor system. Further experiments investigating responsivity of the immune system suggest an increased inflammatory response to arachidonic acid, and enhanced hypothermic response to lipopolysaccharide in prenatally treated offspring. The results are discussed in relation to other manipulations of the maternal milieu, especially prenatal stress. It is concluded that alterations induced by prenatal exposure to ANA, cannabinoids and other psychotropic drugs or prenatal stress, share common features, but the data also suggest specific effects on the ANA-CB receptor system.

Acute-Phase Reaction↗
PubMed1996

Endogenous cannabinoid ligands--chemical and biological studies.

Arachidonic acid ethanolamide (anandamide) is a brain constituent that binds to the brain cannabinoid receptor (CB1). It produces many of the pharmacological effects caused by delta 9-tetrahydrocannabinol (delta 9-THC) in mice. Anandamide parallels delta 9-THC in its specific interaction with the cannabinoid receptor and in inhibition of adenylate cyclase. Two additional fatty acid ethanolamides that bind to the cannabinoid receptor, homo-gamma-linolenylethanolamide and docostetraenylethanolamide, have been identified in the brain. We believe that the anandamides are involved in the coordination of movement and short term memory. Depression of ambulation in an open field and the analgetic response to anandamide are not fully developed until adulthood, possibly due to an age-related increase in the CB1 receptor concentration. This observation has clinical implications in pediatrics. A second cannabinoid receptor (CB2) is present in the spleen. A monoglyceride, 2-arachidonyl-glycerol which binds to both CB1 and CB2 in transfected cells and inhibits andenylate cyclase in spleen cells was found in the gut. Its role is apparently associated with the immune system. These fatty acids amides and esters represent a new family of chemical modulators in the body.

Animals↗
PubMed1995

Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides.

We have previously shown that the endogenous putative cannabinoid ligand arachidonylethanolamide (anandamide, 20:4, n - 6) induces in vivo and in vitro effects typical of a cannabinoid agonist. We now report that two other endogenous anandamides, docosatetraenylethanolamide (anandamide, 22:4, n - 6) and homo-gamma-linolenylethanolamide (anandamide, 20:3, n - 6), have similar activities. The new anandamides bind to SV40-transformed African green monkey kidney cells transfected with the rat brain cannabinoid receptor cDNA and display K1 values of 253.4 +/- 41.1 and 244.8 +/- 38.7, respectively. The value found for arachidonylethanolamide was 155.1 +/- 13.8 nM. In addition, the new anandamides inhibit prostaglandin E1-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells transfected with the cannabinoid receptor, as well as in N18TG2 mouse neuroblastoma cells that express the cannabinoid receptor naturally. The IC50 values for the inhibition of adenylate cyclase in transfected Chinese hamster ovary-K1 cells were 116.8 +/- 8.7 and 109.3 +/- 8.6 nM for docosatetraenylethanolamide and homo-gamma-linolenylethanolamide, respectively. These values were similar to that obtained with arachidonylethanolamide (100.5 +/- 7.7 nM), but were significantly higher than the IC50 value observed with the plant cannabinoid delta9-tetrahydrocannabinol (9.2 +/- 8.6 nM). The inhibitory effects of the anandamides on adenylate cyclase activity were blocked by pertussis toxin, indicating the involvement of pertussis toxin-sensitive GTP-binding protein(s). In a tetrad of behavioral assays for cannabinoid-like effects, the two new anandamides exerted similar behavioral effects to those observed with delta9-tetrahydrocannabinol and arachidonylethanolamide: inhibition of motor activity in an open field, hypothermia, catalepsy on a ring, and analgesia on a hot plate.

Adenylyl Cyclases↗