Full text of DOI:10.1038/sj.bjp.0704466

British Journal of Pharmacology (2002) 135, 181 ± 187
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Antiin¯ammatory action of endocannabinoid
palmitoylethanolamide and the synthetic cannabinoid nabilone in a
model of acute in¯ammation in the rat
2
2
3
1Silvia Conti, Barbara Costa, Mariapia Colleoni, Daniela Parolaro & *,1Gabriella Giagnoni
1Department of Biotechnology and Bioscience, Faculty of Sciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126
2
3
Milan, Italy; Department of Pharmacology, Via Vanvitelli 32, 20129 Milan, Italy and Department of Structural and
Functional Biology, Pharmacology Section, University of Insubria, Via Vanvitelli 32, 20129 Milan, Italy
1
The antiin¯ammatory activity of synthetic cannabinoid nabilone in the rat model of carrageenan-
induced acute hindpaw in¯ammation was compared with that of the endocannabinoid
palmitoylethanolamide and the nonsteroidal antiin¯ammatory drug indomethacin.
2
Preliminary experiments in rats used a tetrad of behavioural tests, speci®c for tetrahydrocanna-
binol-type activity in the CNS. These showed that the oral dose of nabilone 2.5 mg kg71 had no
cannabinoid psychoactivity.
3
Intraplantar injection of carrageenan (1% w v71) elicited a time-dependent increase in paw
volume and thermal hyperalgesia.
Nabilone (0.75, 1.5, 2.5 mg kg71, p.o.), given 1 h before carrageenan, reduced the development
4
of oedema and the associated hyperalgesia in a dose-related manner. Nabilone 2.5 mg kg71
,
palmitoylethanolamide 10 mg kg71 and indomethacin 5 mg kg71, given p.o. 1 h before carrageenan,
also reduced the in¯ammatory parameters in a time-dependent manner.
5
The selective CB2 cannabinoid 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} (SR 144528), 3 mg kg71 p.o.
1 h before nabilone and palmitoylethanolamide, prevented the anti-oedema and antihyperalgesic e€ects of
the two cannabinoid agonists 3 h after carrageenan.
6 Our ®ndings show the antiin¯ammatory e€ect of nabilone and con®rm that of palmitoyletha-
nolamide indicating that these actions are mediated by an uncharacterized CB2-like cannabinoid
receptor.
British Journal of Pharmacology (2002) 135, 181 ± 187
Keywords: Cannabinoids; nabilone; palmitoylethanolamide; in¯ammation; carrageenan oedema; cannabinoid receptor
Abbreviations: COX, cyclo-oxygenase; IL, interleukin; PAF, platelet activating factor; PG, prostaglandin; THC, tetrahydro-
cannabinol; TNF, tumour necrosis factor
Introduction
9
9
8
D -Tetrahydrocannabinol (D -THC), the major psychoactive
component of marijuana, has a wide range of pharmacolo-
gical e€ects, which may have therapeutic value. Despite the
a dimethylheptyl side chain, 11-11-dimethylheptyl-D -THC-11-
oic acid (CT-3), was even more potent and showed analgesic
activity in the mouse hot-plate and phenylquinone-writhing
tests (Burstein et al., 1998) and antiin¯ammatory activity in
acute and chronic models of in¯ammation (Zurier et al.,
1998). After oral administration CT-3 suppressed acute
in¯ammation induced in mice by interleukin-1b (IL-1b) and
tumour necrosis factor a (TNFa) in the subcutaneous air
pouch and reduced the severity of adjuvant-induced poly-
arthritis in the rat. CT-3 suppressed cyclo-oxygenase-2 (COX-
2) activity in 3T3 cells in tissue culture (Zurier et al., 1998)
and, unlike the non-steroidal antiin¯ammatory drug indo-
methacin, did not induce gastrointestinal ulcera when
administered either acutely or chronically (Dajani et al.,
1999).
9
potential therapeutic applications of D -THC, ranging from
analgesia, anti-emesis and appetite stimulation, to anti-
glaucoma properties, its medical use has been limited by its
psychotropic e€ects (Razdan & Howes, 1983; Mechoulam,
1986). In recent years, much e€ort has been made to discover
synthetic analogues that have the medicinal properties
without the psychotropic e€ects.
Among the synthetic derivatives, D8-THC-11-oic acid
(THC-11), orally administered to mice, reduced the oedema
caused by topical application of arachidonic acid on the ear
or by intraplantar injection of platelet activating factor (PAF)
(Burstein et al., 1989). This cannabinoid also inhibited the
production of 5-hydroxyeicosatetraenoic acid, PGE2 and
PGF2a in vitro in mouse peritoneal cells. Its derivative with
The antiin¯ammatory properties of CT-3 were shared by the
endogenous ligand at the CB2 receptor, palmitoylethanolamide
(Showalter et al., 1996; Lambert & Di Marzo, 1999) which has
been proposed as an autacoid to locally reduce mast cell
degranulation, plasma extravasation and hyperalgesia (Aloe et
*Author for correspondence; E-mail: gabriella.giagnoni@unimib.it

182
S. Conti et al
Cannabinoid effects on oedema and hyperalgesia
al., 1993; Mazzari et al., 1996). Mazzari et al. (1996) reported
that orally palmitoylethanolamide reduced carrageenan, for-
malin and dextran-induced oedema, in a time- and dose-
dependent manner, and signi®cantly reduced the mechanical
hyperalgesia provoked by carrageenan. Unlike palmitoyletha-
nolamide, peripheral but not systemic administration of
anandamide, an endogenous agonist at the cannabinoid CB1
receptor isolated from porcine brain (Devane et al., 1992),
inhibited carrageenan-induced oedema and the associated
thermal hyperalgesia in the rat through an interaction with a
peripheral CB1 receptor (Richardson et al., 1998). The
promising results in in¯ammation animal models, suggest
palmitoylethanolamide may o€er a new approach in the
treatment of in¯ammation, but to date the only cannabinoids
evaluate psychoactive cannabinoid-induced e€ects (Compton
et al., 1993). Brie¯y, before oral doses of nabilone (2.5 or
5 mg kg71) or its vehicle (carboxymethylcellulose 1.5% w v71
in saline), then every hour for 3 h, rats were consecutively
tested for body temperature, nociceptive threshold, sponta-
neous locomotor activity and ring immobility. All these
measures were made in a quiet room at a temperature of
22+18C. Body temperature was measured with a rectal
thermistor probe (Ellab, Roedrove, Denmark) inserted to a
constant depth of 5 cm. To determine thermal nociception,
rats were tested for responsiveness to radiant heat with a tail-
¯ick analgesia meter (D'Amour & Smith, 1941) and the
latency to remove the tail from the path of the stimulus
(expressed in seconds) was recorded automatically by a
photoelectric cell. Spontaneous locomotor activity was
counted for 5 min by an Animex activity meter type S
(LKB, Farad Electronics, Hagerstein, Sweden), which
recorded the number of crossings on the magnetic solenoids.
The apparatus was calibrated so it was sensitive to horizontal
movements but not to stereotypic movements (sensitivity
5 mA; intensity of magnetic ®eld 40 mA). Immobility time was
measured by the `ring test' described by Pertwee (1972) with
modi®cations for the rat. The apparatus consisted of a wire
ring, 12 cm in diameter, ®xed horizontally to a ring stand at
a point 38 cm above the desk. The experimenters placed the
rat across the ring, so that it was supported only by its front
and rear paws. Its forepaws were placed on diametrically
opposite points on the ring. The number of seconds the rat
remained motionless on the ring (except for breathing
movements) was recorded. The test was conducted for
5 min and catalepsy was measured as the percentage of the
total time spent on the ring during which the rat remained
immobile.
9
that have obtained drug approval are: D -THC, and a synthetic
derivative of CT-3 nabilone. The former shows analgesic e€ects
in post-operative pain, antiemetic e€ects in cancer patients and
is used to combat weight loss in the acquired immunode®ciency
syndrome (AIDS) by stimulating appetite (Pace et al., 1999).
Nabilone is mainly used against nausea induced by anticancer
drugs, and recently to produce pain relief in multiple sclerosis
(Notcutt et al., 1999; Martyn et al., 1995; Hamann & Di Vadi,
1999). Nabilone consists of the basic cannabinoid nucleus of
D9-THC, with a ketone function in the A ring and a
dimethylheptyl side chain; however, unlike CT-3, the two
methyl groups are attached to the same carbon (Lemberger,
1999). In view of the similarity with the structure of CT-3, the
present study was designed to verify a possible antiin¯amma-
tory and antihyperalgesic role of this compound in carragee-
nan-induced paw oedema, a rat model of in¯ammation.
Methods
Animals
Antiinflammatory and antihyperalgesic assays
Male Wistar rats (100 ± 120 g, Harlan, Italy) were used.
Animals were housed in a room with controlled temperature
(22+18C), humidity (60+10%) and light (12 h per day) for
at least 1 week before being used. Food and water were
available ad libitum. Before the experiments, rats were fasted
overnight, with free access to water. Animal care was in
accordance with the Italian State regulations governing the
care and treatment of laboratory animals (Permission no. 94/
2000A).
Carrageenan-induced oedema and hyperalgesia The antiin-
¯ammatory activity of nabilone, was compared with
palmitoylethanolamide and indomethacin, by measuring the
oedema induced by intraplantar (i. pl.) injection of 0.1 ml
carrageenan (1% w v71 in saline) into the right paw.
Nabilone, at non-psychoactive doses (0.75, 1.5 and
2.5 mg kg71), palmitoylethanolamide (10 mg kg71) and in-
domethacin (5 mg kg71), or an appropriate volume of vehicle
(carboxymethylcellulose 1.5% w v71 in saline) were adminis-
tered orally 1 h before carrageenan. The palmitoylethanola-
mide and indomethacin doses were those Mazzari et al.
(1996) reported were e€ective in reducing carrageenan
oedema. The paw volume was measured with a plethysmo-
meter (Ugo Basile, Va, Italy) immediately before and 1, 2, 3
and 10 h after the intraplantar carrageenan injection. For all
animals both the ipsilateral (injected) and controlateral (non-
injected) hindpaw volume was measured. Oedema was
expressed as the increase in paw volume (ml).
Thermal hyperalgesia was evaluated on the same animals
used to determine the antiin¯ammatory e€ects. Brie¯y, paw
withdrawal latencies were recorded in both hindpaws using
the radiant heat method (Hargreaves et al., 1988). Animals
were placed in a clear acrylic box on a glass platform (Plantar
Test, Ugo Basile, Va, Italy). A beam of radiant heat was
applied through the platform to the plantar surface of the
hindpaw. A photocell detected paw withdrawal and the
Drugs
Drugs were obtained from the following companies: l-
carrageenan (Sigma-Aldrich, Milan, Italy), nabilone (kindly
supplied by Eli Lilly and Co.Ltd., Basingstoke, Hampshire,
U.K.), palmitoylethanolamide (Cayman Chemical, Ann
Arbor, MI, U.S.A.), indomethacin (Sigma-Aldrich, Milan,
Italy) and {N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] hep-
tan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyr-
azole-3-carboxamide} (SR 144528) (kindly supplied by Sano®
Recherche, Montpellier, France).
Psychoactive effects of nabilone
A series of four consecutive observations were conducted on
a standard procedure employed to
each rat, following
British Journal of Pharmacology vol 135 (1)

S. Conti et al
Cannabinoid effects on oedema and hyperalgesia
183
latency was recorded. After paw baseline withdrawal
latencies (s) had been recorded, thermal hyperalgesia was
estimated for each animal 1, 2, 3 and 10 h after carrageenan
injection.
(6.42+0.43 s). This hyperalgesia had disappeared 10 h after
carrageenan, when the latencies were not signi®cantly
di€erent from baseline value (Figure 2b). No di€erences in
paw withdrawal latencies were found in the controlateral
hindpaw at any time after carrageenan (data not shown).
Nabilone (2.5 mg kg71, p.o.) was then employed for a
time-course study in comparison to palmitoylethanolamide
(10 mg kg71, p.o.) and indomethacin (5 mg kg71 p.o.). The
three drugs administered 1 h before carrageenan inhibited
paw oedema at all time points considered; this inhibition was
maximal 3 h after carrageenan injection when the oedema
was reduced by 40, 47 and 60% respectively (Figure 2a).
Hyperalgesia observed at 1, 2, 3 h after carrageenan was also
abolished by all drugs. In rats treated with vehicle the
withdrawal latency for the ipsilateral hindpaw 3 h after
carrageenan injection was 3+0.1, compared to 6.4+0.3,
6.3+0.3 and 6.5+0.3 s in nabilone, palmitoylethanolamide
and indomethacin treated rats (Figure 2b).
Antagonism studies
The selective CB2 cannabinoid receptor antagonist SR
144528, 3 mg kg71 (an oral dose which totally displaced the
ex vivo [3H]-CP55940 binding to the mouse spleen membrane
CB2 receptor, but had no e€ect on the binding of [3H]-
CP55940 to its speci®c sites in the brain: Rinaldi-Carmona et
al., 1998) or its vehicle (10% Tween 80, 20% DMSO in H2O)
was administered orally 1 h before the injection of nabilone
(2.5 mg kg71), palmitoylethanolamide (10 mg kg71) and in-
domethacin (5 mg kg71). One hour later the animals received
an intraplantar injection of 1% carrageenan and the oedema
and thermal hyperalgesia were measured after 3 h.
Statistical analysis
Dose-related anti-oedema and antihyperlagesic effects of
nabilone
The results were expressed as the means+s.e.mean. The data
were analysed using one way analysis of variance (ANOVA)
followed by Tukey's test. Di€erences were considered
signi®cant at P50.05. Linear regression analysis was
calculated using GraphPAD Software, San Diego.
The anti-oedema and antihyperalgesic e€ect of nabilone was
evaluated at the peak time of in¯ammatory response, 3 h
after carrageenan injection. Nabilone (0.75, 1.5 and
2.5 mg kg71
, p.o.) caused a dose-related inhibition of
carrageenan-induced oedema and hyperalgesia (Figure 3a,b).
Oedema was reduced by 8, 28 and 42% respectively and
hyperalgesia was decreased, in fact the paw withdrawal
latencies of the in¯amed paw were increased by 27, 71 and
116%, respectively.
Results
Psychoactive effects of nabilone
In order to select a dose of nabilone with no psychoactive
e€ects, which could be used to study its antiin¯ammatory and
antihyperalgesic activity, rats were tested in the tetrad of
assays employed to evaluate cannabinoid psychoactive e€ects
(Compton et al., 1993). One, two and three hours after oral
doses of nabilone (2.5 and 5 mg kg71) each rat's body
temperature, nociceptive threshold, locomotor activity and
ring immobility were consecutively measured. The behaviour-
al evaluations are given in Figure 1. Rats given 2.5 mg kg71
of nabilone did not show any of these e€ects, whereas the
higher dose (5 mg kg71) caused decreases in body tempera-
ture and motor activity with catalepsy and analgesia. These
e€ects were time-dependent: 3 h after the dose of nabilone
rectal temperature had dropped 2.68C and motor activity by
69%, ring immobility increased by 71% and tail-¯ick latency
increased by 612%.
Antagonism studies
To elucidate whether the anti-oedema and antihyperalgesic
e€ects of nabilone and palmitoylethanolamide were mediated
by the peripheral CB2 cannabinoid receptor, rats were orally
treated with the selective CB2 receptor antagonist SR 144528
(3 mg kg71) 1 h before oral administration of these drugs. To
verify the speci®city of this antagonism, the in¯uence of SR
144528 on the antiin¯ammatory e€ect of indomethacin was
also evaluated. Pretreatment with SR 144528 blocked the
anti-oedema and antihyperalgesic e€ects of nabilone and
palmitoylethanolamide but, as expected, had no e€ect on
those evoked by indomethacin (Figures 4 and 5). SR 144528
on its own did not a€ect carrageenan-induced oedema and
hyperalgesia and oedema and paw withdrawal latency in the
ipsilateral hindpaw did not di€er in vehicle treated animals
(Figures 4 and 5).
Antiinflammatory and antihyperalgesic effects
Before carrageenan injection there was no signi®cant
di€erence in volume and withdrawal latencies between
ipsilateral and controlateral hindpaws (data not shown).
Intraplantar injection of carrageenan 1% w v71 resulted in a
time-related increase in ipsilateral hindpaw volume. One hour
after carrageenan the hindpaw oedema was (0.87+0.15 ml),
at 3 h it peaked and at 10 h it was still present (Figure 2a).
Controlateral hindpaw volume did not change signi®cantly
throughout the experiment (data not shown). Withdrawal
latencies of the ipsilateral hindpaw 1, 2, 3 h after carrageenan
injection were signi®cantly lower than the baseline value
Discussion
The experiments described here con®rmed the antiin¯amma-
tory activity of the endocannabinoid palmitoylethanolamide
(10 mg kg71, p.o.) and for the ®rst time, demonstrated that
the synthetic cannabinoid nabilone, at oral doses with no
psychoactive e€ects, inhibits rat paw carrageenan-induced
oedema in
a dose-dependent fashion. The ecacy of
palmitoylethanolamide in reducing oedema in di€erent
models of acute in¯ammation was already known (Benvenuti
et al., 1968; Mazzari et al., 1996). We showed that the anti-
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184
S. Conti et al
Cannabinoid effects on oedema and hyperalgesia
Figure 1 Time course of behavioural e€ects induced by oral nabilone in the rat. Each point represents the mean+s.e.mean of 3 ± 4
animals. ***P50.001, **P50.01 vs vehicle; ...P50.001, ..P50.01, .P50.05 vs nabilone 2.5 mg kg71
.
oedema e€ect was already evident 1 h after carrageenan,
when oedema formation is dependent on the release of mast
cell mediators (Di Rosa et al., 1971; Al-Haboubi & Zeitlin,
1983); the anti-oedema e€ect was still present at 10 h,
suggesting a lasting ecacy of this cannabinoid. The anti-
oedema activity of nabilone (2.5 mg kg71, p.o.), paralleled
that of palmitoylethanolamide and the classic nonsteroidal
antiiin¯ammatory drug indomethacin (5 mg kg71, p.o.). This
e€ect was already evident 1 h after carrageenan injection, was
higher at 3 h and was still present at 10 h. So far we have
only tested the antiin¯ammatory activity of nabilone in the
model of acute carrageenan induced in¯ammation so we do
not known whether nabilone, as already demonstrated for
palmitoylethanolamide (Mazzari et al., 1996), reduces for-
malin and dextran oedema, which like carrageenan in¯am-
mation, mainly depend on release of mast cell mediators. The
whereas Kosersky et al. (1973) observed this e€ect only at the
high dose of 100 mg kg71, given orally to rats.
Burstein et al. (1992) synthesized a cannabinoid with
analgesic and antiin¯ammatory activities: CT-3. This com-
pound is chemically similar to THC-11, di€ering only in the
substitution of dimethylheptyl chain on C3 instead of the n-
pentyl radical. CT-3 is more than two orders of magnitude
more potent than the template molecule THC-11 in the
rodent paw oedema and hot plate tests (Burstein et al., 1992).
Thus it seems that the dimethylheptyl chain increases the
antiin¯ammatory and analgesic potency of THC. Nabilone
shares a similar structure, di€ering only for the presence of a
ketonic group on C9. Thus it is likely that the dimethylheptyl
chain is also responsible for the anti-oedema e€ect of
nabilone in the model of carrageenan in¯ammation.
Nabilone, like palmitoylethanolamide, inhibited antigen-
induced secretion of serotonin from rat mast cells and
RBL-2H3 cells (Facci et al., 1995). Mast cells release
in¯ammatory mediators such as histamine and serotonin,
9
natural compound D -THC, at doses ranging from 3.75 ±
100 mg kg71, p.o., given to rats 1 h before carrageenan,
always showed an anti-oedema e€ect (So®a et al., 1973)
British Journal of Pharmacology vol 135 (1)

S. Conti et al
Cannabinoid effects on oedema and hyperalgesia
185
Figure 2 E€ect of palmitoylethanolamide (PEA) 10 mg kg71, nabilone (NAB) 2.5 mg kg71 and indomethacin (ID) 5 mg kg71
given orally to the rat 1 h before carrageenan, on oedema (a) and ipsilateral hindpaw withdrawal latency (b) 1, 2, 3 and 10 h after
injection of carrageenan. Each point represents the mean+s.e.mean of 6 ± 9 animals. ***P50.001, *P50.05 vs vehicle.
Figure 3 Dose-response relationships for anti-oedema (a) and antihyperalgesic e€ect (b) of nabilone orally administered in the rat
1 h before carrageenan. The response was measured at 3 h after injection of carrageenan. Each symbol represents the
mean+s.e.mean of four animals.
involved in vasodilatation, increased vascular permeability
and activation of nociceptors. It remains to be ascertained
whether nabilone reduces carrageenan-induced oedema by
modulating mast cell degranulation.
1999; Calignano et al., 1998; 2001). In our hands
palmitoylethanolamide also abolished the thermal hyperalge-
sia evoked by carrageenan.
The activation of CB2 receptor appears to be involved in
downregulation of the in¯ammatory response (Aloe et al.,
1993; Facci et al., 1995; Mazzari et al., 1996). This is
supported by experimental evidence that the CB2 cannabi-
noid receptor antagonist SR 144528 reduced the antiin-
¯ammatory and analgesic e€ects of the selective CB2
cannabinoid receptor agonist HU-308 (Hanus et al., 1999)
and also prevented palmitoylethanolamide-evoked antihyper-
algesia (Calignano et al., 1998; 2001).
We demonstrated here that nabilone has dose-dependent
action in reducing not only oedema but also hyperalgesia,
supporting the clinical data showing that this compound
relieves the severe and intractable pain of muscle spasm in
multiple sclerosis (Hamann & Di Vadi, 1999; Martyn et al.,
1995). These ®ndings are consistent with the ability of
palmitoylethanolamide and other cannabinoids to reduce
hyperalgesia in rodent models of acute in¯ammation induced
by various agents, such as carrageenan, formalin, kaolin,
acetic acid and magnesium sulphate (Mazzari et al., 1996;
Jaggar et al., 1998; Richardson et al., 1998; Hanus et al.,
To ascertain whether the anti-oedema and antihyperalgesic
e€ects of nabilone and palmitoylethanolamide were mediated
by a peripheral cannabinoid receptor, we employed the CB2
British Journal of Pharmacology vol 135 (1)

186
S. Conti et al
Cannabinoid effects on oedema and hyperalgesia
palmitoylethanolamide but did not a€ect oedema and
hyperalgesia. It has been reported that systemically adminis-
tered SR 144528 enhanced formalin-induced pain responses
in mice only in the early phase (Calignano et al., 1998). In
agreement with Calignano et al. (1998), we found that 5 min
after carrageenan, SR 144528 by itself evoked
a pain
behaviour (licking and ¯exing of the treated limb) (data not
shown). Even so, the production of hyperalgesia by SR
144528 is unlikely to account for its ability to prevent the
cannabinoid-induced antihyperalgesic e€ect, 3 h after carra-
geenan.
Figure 4 E€ect of SR 144528 (SR) 3 mg kg71, p.o. in the rat 1 h
before palmitoylethanolamide (PEA) 10 mg kg71 p.o., nabilone
(NAB) 2.5 mg kg71 p.o., indomethacin (ID) 5 mg kg71 p.o. or
vehicle, on oedema 3 h after injection of carrageenan. Each point
represents the mean+s.e.mean of 10 ± 15 animals. ***P50.001,
**P50.01 vs vehicle; +P50.05 vs PEA; ^^P50.01 vs NAB.
Nabilone has the same anity for human CB1 and CB2
receptors (Gareau et al., 1996). Theoretically, the drug could
therefore alleviate pain by acting at peripheral CB1 receptors
on nociceptive neurons, without any recruitment of brain
CB1 receptors, since at 2.5 mg kg71 it did not have central
e€ects. However, our ®ndings seem to exclude CB1 receptor
involvement and point more to a role of CB2 receptors, since
SR 144528 completely prevented nabilone-induced antihyper-
algesia. It remains to be seen how a dose unable to activate
CB1 receptors can exclusively bind the CB2 receptor. At the
moment, we do not understand why this happens, but one
possible explanation is that nabilone may bind and activate a
not-yet characterized CB2-like receptor, reported by Caligna-
no et al. (1998) to be sensitive to SR 144528; this receptor
may also mediate the antiin¯ammatory e€ects of palmitoyle-
thanolamide (Calignano et al., 1998; 2001), which does not
bind with high anity to either of the two cannabinoid
receptor subtypes (Lambert & Di Marzo, 1999).
In conclusion, our ®ndings indicate that nabilone and
palmitoylethanolamide have a peripheral antiin¯ammatory
e€ect mediated by an uncharacterized CB2-like receptor.
However, the biochemical mechanisms underlying the
antiin¯ammatory action of palmitoylethanolamide and
nabilone and whether these cannabinoids are also active
once in¯ammation has started remains to be clari®ed.
Figure 5 E€ect of SR 144528 (SR) 3 mg kg71, p.o. in the rat 1 h
before palmitoylethanolamide (PEA) 10 mg kg71 p.o., nabilone
(NAB) 2.5 mg kg71 p.o., indomethacin (ID) 5 mg kg71 p.o. or
vehicle, on ipsilateral hindpaw withdrawal latency 3 h after injection
of carrageenan. Baseline hindpaw withdrawal latencies measured
before carrageenan were not di€erent from each other. Thus in the
®gure the base indicates the baseline ipsilateral hindpaw withdrawal
latencies of vehicle-treated rats. Each point represents the mean+
s.e.mean of 10 ± 15 animals. ***P50.001 vs vehicle; ...P50.001,
..P50.01 vs base; +++P50.001 vs PEA; ^^P50.01 vs NAB.
This work was supported by grants from Italian National
Research Council (C.N.R.) and from Italian Ministry for Uni-
versity and Scienti®c and Technological Research (M.U.R.S.T.).
The authors thank Eli Lilly and Co. Ltd., Basingstoke, Hampshire,
U.K. for the gift of nabilone; Dr Francis Barth (Sano® Recherche,
Montpellier, France) for the gift of SR 144528 and Judy Baggott
for style revision.
cannabinoid receptor antagonist SR 144528 (Rinaldi-Carmo-
na et al., 1998). This antagonist completely prevented the
anti-oedema and antihyperalgesic e€ects of nabilone and
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(Received February 19, 2001
Revised August 6, 2001
Accepted October 29, 2001)
British Journal of Pharmacology vol 135 (1)