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The Journal of Neuroscience, November 1, 2002, 22(21):9612-9617
A Peripheral Mechanism for CB1 Cannabinoid
Receptor-Dependent Modulation of Feeding
Raquel
Gómez1,
Miguel
Navarro1,
Belén
Ferrer2,
José M.
Trigo1,
Ainhoa
Bilbao2,
Ignacio
Del Arco2,
Andrea
Cippitelli2,
Felice
Nava3,
Daniele
Piomelli3, and
Fernando
Rodríguez de Fonseca2
1 University Institute of Drug Dependencies, Department
of Psychobiology, University Complutense of Madrid, Madrid
28223, Spain, 2 Fundación de Investigación
Carlos Haya, Hospital Universitario Carlos Haya, Málaga 29010, Spain, and 3 Department of Pharmacology, University of
California, Irvine, California 92697-4625
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ABSTRACT |
Recent studies suggest that the endocannabinoid system modulates
feeding. Despite the existence of central mechanisms for the regulation of food intake by endocannabinoids, evidence indicates that peripheral mechanisms may also exist. To test this hypothesis, we
investigated (1) the effects of feeding on intestinal anandamide accumulation; (2) the effects of central (intracerebroventricular) and
peripheral (intraperitoneal) administration of the endocannabinoid agonist anandamide, the synthetic cannabinoid agonist
R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate (WIN55,212-2), and the CB1-selective antagonist
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A) on food intake in rats; and (3) the effects of sensory deafferentation on the modulation of feeding by cannabinoids. Food
deprivation produced a sevenfold increase in anandamide content in the
small intestine but not in the brain or stomach. Refeeding normalized
intestinal anandamide levels. Peripheral but not central administration
of anandamide or WIN55,212-2 promoted hyperphagia in partially satiated
rats. Similarly, peripheral but not central administration of SR141716A
reduced food intake. Capsaicin deafferentation abolished the peripheral
effects of both cannabinoid agonists and antagonists, suggesting that
these agents modulate food intake by acting on CB1 receptors located on
capsaicin-sensitive sensory terminals. Oleoylethanolamide, a
noncannabinoid fatty ethanolamide that acts peripherally, prevented
hyperphagia induced by the endogenous cannabinoid anandamide.
Pretreatment with SR141716A enhanced the inhibition of feeding induced
by intraperitoneal administration of oleoylethanolamide. The results
reveal an unexpected role for peripheral CB1 receptors in the
regulation of feeding.
Key words:
anandamide; cannabinoid; capsaicin; cholecystokinin; food
intake; rat; satiety; SR141716A; WIN55,212-2
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INTRODUCTION |
Historical descriptions of the
stimulatory effects of Cannabis sativa on feeding are now
explained by the ability of its psychoactive constituent
 9-tetrahydrocannabinol (THC) to
interact with CB1 cannabinoid receptors (Williams et al., 1998 ;
Kunos and Batkai, 2001). Both THC and the endogenous cannabinoid
anandamide (AEA) (Devane et al., 1992) promote overeating in
partially satiated rats (Williams and Kirkham, 1999). Moreover, THC
increases fat intake in laboratory animals and stimulates appetite in
humans (Sacks et al., 1990; Williams et al., 1998; Koch, 2001). The
selective CB1 receptor antagonist SR141716A (Rinaldi-Carmona et al.,
1995) counteracts these effects and, when administered alone, decreases
standard chow intake and caloric consumption (i.e., sucrose or ethanol
intake), presumably by antagonizing the actions of endogenously
released endocannabinoids such as anandamide and 2-arachidonoylglycerol
(Arnone et al., 1997; Colombo et al., 1998; Simiand et al, 1998;
Kirkham and Williams, 2001; Rowland et al., 2001). These results
suggest that endocannabinoid substances may play a role in the
promotion of food intake, possibly by delaying satiety.
It is generally thought that the hyperphagic actions of cannabinoids
are mediated by CB1 receptors located in brain circuits involved in the
regulation of motivated behaviors (Herkenham et al., 1991). Thus,
infusions of anandamide in the ventromedial hypothalamus were shown to
promote hyperphagia (Jamshidi and Taylor, 2001), whereas the anorectic
effects of leptin were found to be associated with a decrease in
hypothalamic anandamide levels (Di Marzo et al., 2001). Nevertheless,
evidence suggests that cannabinoids also may promote feeding by acting
at peripheral sites. Indeed, CB1 receptors are found on nerve terminals
innervating the gastrointestinal tract (Croci et al., 1998; Hohmann
and Herkenham, 1999), which are known to be involved in mediating
satiety signals that originated in the gut (Reidelberger, 1992).
To test this hypothesis, in the present study we have examined (1) the
impact of feeding on intestinal anandamide accumulation, (2) the
effects of central versus peripheral systemic administration of
cannabinoid receptor agonists on feeding behavior, and (3) the effects
of sensory deafferentation on cannabinoid-induced hyperphagia.
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MATERIALS AND METHODS |
Animals. Male Wistar rats (350 ± 50 gm) were
housed individually with food and water available ad
libitum, except when restriction was required. All animal
procedures met the National Institutes of Health guidelines for the
care and use of laboratory animals and the European Communities
directive 86/609/EEC regulating animal research.
Surgery. For intracerebroventricular injections,
stainless steel guide cannulas aimed at the lateral ventricle were
implanted in the rats. The animals were anesthetized with equithesin
and placed in a David Kopf Instruments (Tujunga, CA) stereotaxic
instrument with the incisor bar set at 5 mm above the interaural line.
A guide cannula (7 mm, 23 gauge) was secured to the skull by using two
stainless steel screws and dental cement and was closed with 30 gauge
obturators (Navarro et al., 1996; Rodríguez de Fonseca et al.,
2001). The implantation coordinates were 0.6 mm posterior to bregma,
±2.0 mm lateral, and 3.2 mm below the surface of the skull. These
coordinates placed the cannula 1 mm above the ventricle. After a 7 d postsurgical recovery period, cannula patency was confirmed by
gravity flow of isotonic saline through an 8-mm-long, 30 gauge injector
inserted within the guide to 1 mm beyond its tip. This procedure
allowed the animals to become familiar with the injection technique.
Chemicals. Capsaicin was purchased from Sigma
(St. Louis, MO), and cholecystokinin octapeptide sulfated (CCK-8),
R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate (WIN55, 212-2), and
1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP93129) were obtained from Tocris Cookson (Bristol, UK).
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A) was a gift from Sanofi Recherche (Montpellier, France). Anandamide and oleoylethanolamide (OEA) were synthesized in the laboratory (Giuffrida et al., 2000). Capsaicin was dissolved in 5%
Tween 80, 5% propyleneglycol, and 90% saline. All other drugs were dissolved in dimethylsulfoxide (DMSO) and administered in 70%
DMSO in sterile saline.
HPLC/mass spectrometry analyses. Anandamide was
solvent-extracted from tissues, fractionated by column chromatography,
and quantified by HPLC/mass spectrometry with an isotope dilution method, as described previously (Giuffrida et al., 2000).
Drug treatments. Capsaicin was administered subcutaneously
(12.5 mg/ml) (Kaneko et al., 1998) in rats anesthetized with ethyl ether. The total dose of capsaicin (125 mg/kg) was divided into three
injections (25 mg/kg in the morning and 50 mg/kg in the afternoon, and
then 50 mg/kg on the next day). Control rats received vehicle
injections. Experiments were performed 10 d after capsaicin treatment in rats that (1) had lost the corneal chemosensory reflex (eye wiping for 1-3 min after application of 0.1% ammonium hydroxide into one eye), and (2) showed enhanced water intake 10 d after capsaicin treatment. Water intake (in milliliters per 4 hr) was as
follows: vehicle, 13.6 ± 1.4; capsaicin rats, 24.0 ± 1.9, p < 0.01 (n = 12). The associated food
intake (grams per 4 hr) was as follows: vehicle, 11.9 ± 0.6;
capsaicin rats, 10.9 ± 0.7.
Drugs were administered by intraperitoneal injection 15 min before food
presentation in a volume of 1 ml/kg. For intracerebroventricular administration, the obturator was removed from the guide cannula and an
8 mm injector (30 gauge stainless steel tubing) that was connected to
70 cm of calibrated polyethylene-10 tubing was lowered into the
ventricle. The tubing was then raised until flow began, and 5 µl of
drug solution was infused over a 30-60 sec period. The injector was
left in the guide cannula for an additional 30 sec and then removed.
The stylet was immediately replaced. Animals were tested 5 min after
injections. The intracerebroventricular cannula placements were
evaluated after each experiment by dye injection. Only rats with proper
intracerebroventricular placements were included in the data analysis.
Food intake studies. The effects of drugs on feeding
behavior were analyzed in animals deprived of food for 24 hr and
habituated to handling (Navarro et al., 1996; Rodríguez de
Fonseca et al., 2001) or in partially satiated animals (i.e., 24 hr
food-deprived animals allowed to eat for 60 min before drug testing)
(Williams et al., 1998). To this end, 48 hr before testing, the bedding material was removed from the cage and a small can containing food
pellets was placed inside the cage for 4 hr. The animals were then
food-deprived for 24 hr, with access to water ad libitum. The animals were returned to their home cage 15 min after drug administration; there, a can with a measured amount of food (usually 30-40 gm) and a bottle containing 250 ml of fresh water were placed. Food pellets and food spillage were weighed at 60, 120, and 240 min
after starting the test, and the amount of food eaten was recorded. At
the end of the test, the amount of water consumed was also measured.
For partial satiation of animals, 24 hr food-deprived rats were allowed
to eat from the can for 1 hr. The can was replaced and intake was
recorded. Fifteen minutes after drug injections, the food was again
presented, and the amount consumed was recorded hourly for the next 4 hr.
Open-field test. Motor behaviors in the open field were
studied in an opaque open field (100 × 100 × 40 cm) as described previously
(Beltramo et al., 2000). The field was illuminated using a ceiling
halogen lamp regulated to yield 350 lux at the center of the field.
Rats were habituated to the field for 10 min the day before testing. On
the experimental day, the animals were treated and placed in the center
of the field, and locomotor activity (number of lines crossed) and
rearing and grooming behavior (number of rearings and time spent in the center of the field) were scored for 5 min at 5, 30, 60, and 120 min
after drug injection. Behavior was scored by trained observers who were
unaware of the experimental conditions.
Statistics. Statistical significance was assessed by one-way
or multifactorial ANOVA, as required. After a significant F
value, post hoc analysis (Student-Newman-Keuls test) was
performed. Calculations were done using the BMDP statistical
package (SPSS Inc., Chicago, IL).
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RESULTS |
Effects of feeding on anandamide levels
We first investigated whether starvation and refeeding affect
anandamide content in intestinal tissue, where various intrinsic signals modulating food intake, such as CCK (Reidelberger, 1992) and
OEA (Rodríguez de Fonseca et al., 2001), are generated. As shown in Figure 1, food deprivation (24 hr) was accompanied by a sevenfold increase in anandamide content in
the small intestine, an effect that was reversed on refeeding. In
contrast, no such increase was observed in brain or stomach tissues
(Fig. 1) (data not shown). The change in intestinal anandamide did not
result from the inhibition of anandamide degradation. Indeed, fatty
acid amidohydrolase activity, which catalyzes the deactivating
hydrolysis of anandamide, was not affected by the feeding status (data
not shown).
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Figure 1.
Effects of starvation and feeding on anandamide
levels in the brain and small intestine. Starvation promoted the
accumulation of anandamide in the small intestine. Data are the
means ± SEM of at least five determinations per group.
**p < 0.01, fed versus starved group;
Newman-Keuls.
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Central cannabinoid administration does not affect food intake
As reported previously (Williams et al., 1998), intraperitoneal
administrations of the endogenous cannabinoid anandamide or the
synthetic cannabinoid agonist WIN55,212-2 (0.1-2 mg/kg) had no effect
on food intake in food-deprived rats (data not shown). Nevertheless,
when administered to partially satiated animals, these drugs elicited
significant and prolonged hyperphagia (Fig. 2A,C). At a dose of 10 mg/kg, WIN55,212-2 also produced profound immobility, which interfered
with feeding behavior (Fig. 2C). In contrast, central
injections of anandamide and WIN55,212-2 had no effect on feeding,
except at the highest dose (10 µg), which resulted in motor
impairment (Fig. 2B,D) (data not shown).
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Figure 2.
Peripheral effects of cannabinoids on
food intake. A, AEA elicited hyperphagia in partially
satiated animals when injected after a 60 min meal. B,
Anandamide has no effect after intracerebroventricular administration.
C, Acute intraperitoneal injection of WIN55,212-2
(WIN) promoted hyperphagia in partially satiated
animals. D, WIN55,212-2 had no effect after
intracerebroventricular injection. E, Acute
intraperitoneal injection of SR141716A (SR) reduced food
intake in food-deprived rats during the 240 min testing period.
F, The intracerebroventricular administration of
SR141716A did not affect food intake in food-deprived animals. Data are
means ± SEM of at least 10 determinations per group.
*p < 0.01 versus vehicle-treated group
(white bars); Newman-Keuls.
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After systemic administration, the selective CB1 antagonist
SR141716A elicited a dose-dependent reduction of food intake in both 24 hr food-deprived rats (Fig. 2E) and partially
satiated rats (data not shown). However, the drug had no effect after
central administration (Fig. 2F). Regardless of the
administration route, SR141716A reduced rearing behavior and increased
grooming (Table 1) in the open field,
indicating that the drug effectively interacted with brain cannabinoid
receptors (Navarro et al., 1997). The results suggest that the
hyperphagia evoked by cannabinoid receptor agonists, as well as the
anorexia elicited by the CB1 antagonist SR141716A, may be dependent on
the interaction of these agents with peripheral cannabinoid
receptors. Additional experiments were done with the CB2 receptor
antagonist
N-[(1S)-endo-1,3,3-trimethyl
bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528). As reported previously (Rodríguez de
Fonseca et al., 2001), blockade of CB2 receptors did not affect
feeding. Moreover, pretreatment with SR144528 did not affect
WIN55,212-2-induced hyperphagia (data not shown).
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Table 1.
Effects of either central (intracerebroventricular) or
peripheral (intraperitoneal) administration of vehicle and the CBl
cannabinoid receptor antagonist SR141716A on motor behaviors measured
in the open field
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Sensory deafferentation prevents cannabinoid effects
on feeding
Treatment with the neurotoxin capsaicin abolished the anorexic
response elicited by the peptide CCK-8 (10 µg/kg, i.p.) but not that
induced by the centrally acting 5-HT-1B agonist
CP93129 (1 mg/kg, i.p.) (Fig.
3A), indicating that sensory
terminals innervating the gut had been destroyed. The treatment also
resulted in a loss of the hyperphagic effects of either WIN55,212-2 (2 mg/kg, i.p.) (Fig. 3B) or anandamide (2 mg/kg, i.p.) (data
not shown) and of the hypophagic effects of SR141716A (3 mg/kg, i.p.)
(Fig. 3C).
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Figure 3.
A, Capsaicin treatment abolished
the anorexic effect of CCK-8, which acts peripherally, but not that of
the 5-HT-1B agonist CP93129, which acts centrally.
B, WIN55,212-2 (WIN) did not
produce hyperphagia in capsaicin-treated rats. C,
Capsaicin treatment abolished the reduction of food intake elicited by
SR141716A (SR) in food-deprived rats.
VEH, Vehicle. Data are the means ± SEM of at least
10 determinations per group. *p < 0.01 versus
vehicle-treated group; Newman-Keuls.
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SR141716A and OEA synergistically inhibit feeding
The small intestine produces both anandamide, which stimulates
food intake (Williams and Kirkham, 1999), and OEA, which inhibits food
intake by acting on peripheral sensory fibers (Rodríguez de
Fonseca et al., 2001). However, the intestinal levels of the two
compounds appear to be reciprocally regulated. Thus, the OEA content
decreases (Rodríguez de Fonseca et al., 2001), whereas the
anandamide content increases (present study) during starvation. To
examine the possible interaction of these fatty acid ethanolamides on
feeding, we studied (1) whether OEA blocks AEA-induced hyperphagia and
(2) whether blockade of CB1 receptors with a low, subthreshold dose of
SR141716A potentiates the inhibitory actions of OEA on food intake. The
results, illustrated in Figure
4A, indicate that pretreatment with OEA inhibits AEA-induced hyperphagia in partially satiated rats, whereas SR141716A and OEA act synergistically to decrease eating in food-deprived animals (Fig. 4B).
The effects were observed during the 240 min period of testing. The
inhibitory actions of combined SR141716A and OEA lasted for at least 24 hr (data not shown), a prolonged effect that these drugs do not elicit separately.
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Figure 4.
A, OEA blocked hyperphagia elicited
by AEA (10 mg/kg) when injected 30 min before the endogenous
cannabinoid in partially satiated rats. VEH, Vehicle.
B, SR141716A (SR) potentiates the feeding
suppression induced by OEA. The effects of a subthreshold dose of
SR141716A (0.3 mg/kg, i.p.) on OEA (0.5, 1, and 5 mg/kg, i.p.) induced
feeding suppression on food intake in 24 hr food-deprived rats 1 hr
after the injection of OEA. Either vehicle (open bars)
or SR141716A (black bars) was injected 30 min
before OEA. Similar results were obtained 4 and 24 hr after the
administration of drugs (data not shown). Data are the means ± SEM of at least 10 determinations per group. *p < 0.01 versus vehicle-treated group; Newman-Keuls.
#p < 0.01 versus 0 dose.
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DISCUSSION |
The present results suggest, first, that systemically administered
cannabinoid agents (both agonists and antagonists) affect food intake
predominantly by engaging peripheral CB1 receptors localized to
capsaicin-sensitive sensory terminals and, second, that intestinal
anandamide is a relevant signal for the regulation of feeding.
Two observations support the idea that cannabinoid agents modulate
feeding through a peripheral mechanism. First, the lack of effect
of central administration of cannabinoid antagonists such as
SR14116A (present data) and
6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-[1H]-indol-3-yl (4-methoxyphenyl) methanone (Koch and Werner, 2000) on food
intake in food-deprived animals and, second, the ability of
capsaicin-induced deafferentation to prevent changes in feeding
elicited by the peripheral administration of cannabinoid drugs.
Moreover, the similar pattern of expression of the early gene
c-fos on hypothalamic and brainstem areas regulating food
intake after both the peripheral administration of either CB1 agonists
and antagonists (Rodríguez de Fonseca et al., 1997) and the
acute administration of peripherally acting satiety modulators such as
gastrointestinal hormones (Turton et al., 1996) or feeding inhibitors
such as OEA (Rodríguez de Fonseca et al., 2001) further support
the peripheral actions of cannabinoids on food intake. Finally, the
fact that the CB1 receptor antagonist SR141716A was active only after
intraperitoneal or oral administration but not after subcutaneous
injection (Rowland et al., 2001) further supports this hypothesis.
These results do exclude the possibility that peripheral anandamide
also modulates feeding by acting on specific hypothalamic areas
involved in caloric homeostasis (such as the ventromedial, arcuate, or
paraventricular hypothalamic nuclei) (Di Marzo et al., 2001; Jamshidi
and Taylor, 2001). However, they do suggest that the predominant
effects of systemically administered SR141716A are mediated by
peripheral CB1 receptors, which may thus represent a potential target
for anorexic agents.
The concentration of anandamide in intestinal tissue increases during
food deprivation, reaching levels that are threefold greater than those
needed to half maximally activate CB1 receptors (Devane et al., 1992).
This surge in anandamide levels, the mechanism of which is unknown, may
serve as a short-range hunger signal to promote feeding. This idea is
supported by the ability of SR141716A to reduce food intake after
systemic but not central administration. Locally produced anandamide
also may be involved in the regulation of gastric emptying and
intestinal peristalsis, two processes that are inhibited by this
endocannabinoid (Calignano et al., 1997; Izzo et al., 1999). Thus,
intestinal anandamide appears to serve as an integrative signal that
concomitantly regulates food intake and gastrointestinal motility.
The predominant peripheral component of feeding suppression induced by
SR141716A led us to analyze whether the modulation of food intake
derived from CB1 receptor stimulation/blockade may interact with that
produced by the noncannabinoid anandamide analog OEA (Rodríguez
de Fonseca et al., 2001). Our results indicate that the hyperphagic
effects elicited by CB1 receptor stimulation were counteracted by the
administration of OEA, whereas CB1 receptor blockade potentiates the
suppression of feeding evoked by OEA. Because the intestinal levels of
anandamide and OEA are inversely correlated (OEA increases after a
meal, which results in a decrease in anandamide levels; anandamide
increases during starvation, associated with a profound decrease in
intestinal OEA) (Rodríguez de Fonseca et al., 2001; and present
data), it is tempting to speculate that both compounds act in a
coordinated manner to control feeding responses through their opposing
actions on sensory nerve terminals within the gut.
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FOOTNOTES |
Received March 29, 2002; revised Aug. 9, 2002; accepted Aug. 16, 2002.
This work was supported by Fundación Rodríguez Pascual;
Ministerio de Ciencia y Tecnología, Fondo de
Investigación Sanitaria 2002/0001; Plan Nacional Sobre Drogas and
Del Amo Program-Universidad Complutense de Madrid (M.N. and F.R.F.);
and by the National Institute on Drug Abuse (D.P.). We thank Dr. M. Mossé (Sanofi Research) for generously providing SR141716A.
Correspondence should be addressed to either of the following: Fernando
Rodríguez de Fonseca, Hospital Carlos Hay Foundation, Carlos
Haya Avenue 82, Seventh floor, Pavillion A, 29010 Málága, Spain,
E-mail: frfonseca{at}hch.sas.junta-andalucia.es; or Miguel Navarro,
Department of Psychobiology, Faculty of Psychology, Complutense University, 28040 Madrid, Spain, E-mail: mnavarro{at}psi.ucm.es.
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REFERENCES |
-
Arnone M,
Maruani J,
Chaperon F,
Thiebot MH,
Poncelet M,
Soubrie P,
Le Fur G
(1997)
Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors.
Psychopharmacology
132:104-106[Medline].
-
Beltramo M,
Rodríguez de Fonseca F,
Navarro M,
Calignano A,
Gorriti MA,
Grammatikopoulus G,
Sadile G,
Giuffrida A,
Piomelli D
(2000)
Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor.
J Neurosci
20:3401-3407[Abstract/Free Full Text].
-
Calignano A,
La Rana G,
Makriyannis A,
Lin SY,
Beltramo M,
Piomelli D
(1997)
Inhibition of intestinal motility by anandamide, an endogenous cannabinoid.
Eur J Pharmacol
340:R7-R8[ISI][Medline].
-
Colombo G,
Agabio R,
Fa M,
Guano L,
Lobina C,
Loche A,
Reali R,
Gessa GL
(1998)
Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716.
Alcohol Alcohol
33:126-130[Abstract/Free Full Text].
-
Croci T,
Manara L,
Aureggi G,
Guagnini F,
Rinaldi-Carmona M,
Manfrand JP,
Le Fur G,
Mukenge S,
Ferla G
(1998)
In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum.
Br J Pharmacol
125:1393-1395[ISI][Medline].
-
Devane WA,
Hanus L,
Breuer A,
Pertwee RG,
Stevenson LA,
Griffin G,
Gibson D,
Mandelbaum A,
Etinger A,
Mechoulam R
(1992)
Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Science
258:1946-1949[Abstract/Free Full Text].
-
Di Marzo V,
Goparaju SK,
Wang L,
Liu J,
Batkai S,
Jarai Z,
Fezza F,
Miura GI,
Palmiter RD,
Sugiura T,
Kunos G
(2001)
Leptin-regulated endocannabinoids are involved in maintaining food intake.
Nature
410:822-825[Medline].
-
Giuffrida A,
Rodríguez de Fonseca F,
Piomelli D
(2000)
Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry.
Anal Biochem
280:87-93[ISI][Medline].
-
Herkenham M,
Lynn AB,
Johnson MR,
Melvin LS,
de Costa BR,
Rice KC
(1991)
Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study.
J Neurosci
11:563-583[Abstract].
-
Hohmann AG,
Herkenham M
(1999)
Localization of central cannabinoid receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study.
Neuroscience
90:923-931[ISI][Medline].
-
Izzo AA,
Mascolo N,
Capasso R,
Germano MP,
De Pasquale R,
Capasso F
(1999)
Inhibitory effect of cannabinoid agonists on gastric emptying in the rat.
Naunyn Schmiedebergs Arch Pharmacol
360:221-223[Medline].
-
Jamshidi N,
Taylor DA
(2001)
Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats.
Br J Pharmacol
134:1151-1154[ISI][Medline].
-
Kaneko H,
Kaunitz J,
Tache Y
(1998)
Vagal mechanisms underlying gastric protection induced by chemical activation of raphe pallidus in rats.
Am J Physiol
275:G1056-G1062[Abstract/Free Full Text].
-
Kirkham TC,
Williams CM
(2001)
Synergistic effects of opioid and cannabinoid antagonists on food intake.
Psychopharmacology
153:267-270[Medline].
-
Koch JE
(2001)
Delta(9)-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets.
Pharmacol Biochem Behav
68:539-543[ISI][Medline].
-
Koch JE,
Werner NA
(2000)
Effects of the cannabinoid antagonists AM 630 and AM 281 on deprivation-induced food intake in Lewis rats.
Soc Neurosci Abstr
26:1528.
-
Kunos G,
Batkai S
(2001)
Novel physiologic functions of endocannabinoids as revealed through the use of mutant mice.
Neurochem Res
26:1015-1021[Medline].
-
Navarro M,
Rodríguez de Fonseca F,
Alvarez E,
Chowen JA,
Zueco JA,
Gómez R,
Eng J,
Blázquez E
(1996)
Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake.
J Neurochem
67:1982-1991[ISI][Medline].
-
Navarro M,
Hernández E,
Muñoz RM,
del Arco I,
Villanúa MA,
Carrera MR,
Rodríguez de Fonseca F
(1997)
Acute administration of the CB1 cannabinoid receptor antagonist SR 141716 A induces anxiety-like responses in the rat.
NeuroReport
8:491-496[ISI][Medline].
-
Reidelberger RD
(1992)
Abdominal vagal mediation of the satiety effects of exogenous and endogenous cholecystokinin in rats.
Am J Physiol
263:R1354-R1358[Abstract/Free Full Text].
-
Rinaldi-Carmona M,
Barth F,
Heaulme M,
Alonso R,
Shire D,
Congy C,
Soubrie P,
Breliere JC,
Le Fur G
(1995)
Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist.
Life Sci
56:1941-1947[ISI][Medline].
-
Rodríguez de Fonseca F,
Carrera MR,
Navarro M,
Koob GF,
Weiss F
(1997)
Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal.
Science
276:2050-2054[Abstract/Free Full Text].
-
Rodríguez de Fonseca F,
Navarro M,
Alvarez E,
Roncero I,
Chowen JA,
Maestre O,
Gómez R,
Muñoz RM,
Eng J,
Blázquez E
(2000)
Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats.
Metabolism
49:709-717[ISI][Medline].
-
Rodríguez de Fonseca F,
Navarro M,
Gómez R,
Escuredo L,
Nava F,
Fu J,
Murillo-Rodríguez E,
Giuffrida A,
LoVerme J,
Gaetani S,
Kathuria S,
Gall C,
Piomelli D
(2001)
An anorexic lipid mediator regulated by feeding.
Nature
414:209-212[Medline].
-
Rowland NE,
Mukherjee M,
Robertson K
(2001)
Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats.
Psychopharmacology
159:111-116[Medline].
-
Sacks N,
Hutcheson Jr JR,
Watts JM,
Webb E
(1990)
Case report: the effect of tetrahydrocannabinol on food intake during chemotherapy.
J Am Coll Nutr
9:630-632[Medline].
-
Simiand J,
Keane M,
Keane PE,
Soubrie P
(1998)
SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset.
Behav Pharmacol
9:179-181[ISI][Medline].
-
Turton MD,
O'Shea D,
Gunn I,
Beak SA,
Edwards CM,
Meeran K,
Choi SJ,
Taylor GM,
Heath MM,
Lambert PD,
Wilding JP,
Smith DM,
Ghatei MA,
Herbert J,
Bloom SR
(1996)
A role for glucagon-like peptide-1 in the central regulation of feeding.
Nature
79:69-72.
-
Williams CM,
Kirkham TC
(1999)
Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors.
Psychopharmacology
143:315-317[Medline].
-
Williams CM,
Rogers PJ,
Kirkham TC
(1998)
Hyperphagia in pre-fed rats following oral delta9-THC.
Physiol Behav
65:343-346[Medline].
Copyright © 2002 Society for Neuroscience 0270-6474/02/22219612-06$05.00/0
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|
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|
|
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|
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|
|
|
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|
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|
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|
|
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|
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|
|
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|
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