European Journal of Neuroscience

European Journal of Neuroscience, Vol. 39, pp. 485–500, 2014 doi:10.1111/ejn.12468

Involvement of the endocannabinoid system in

osteoarthritis pain

Carmen La Porta,* Simona A. Bura,* Roger Negrete and Rafael Maldonado

ncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Dr. Aiguader, 88,
Laboratori de Neurofarmacologia, Facultat de Cie
Barcelona 08003, Spain

Keywords: analgesia, cannabinoid, nociception, osteoarthritis, pain

Abstract
Osteoarthritis is a degenerative joint disease associated with articular cartilage degradation. The major clinical outcome of osteo-
arthritis is a complex pain state that includes both nociceptive and neuropathic mechanisms. Currently, the therapeutic
approaches for osteoarthritis are limited as no drugs are available to control the disease progression and the analgesic treatment
has restricted efficacy. Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an
emerging therapeutic target for osteoarthritis pain. Indeed, pharmacological studies have shown the anti-nociceptive effects of
cannabinoids in different rodent models of osteoarthritis, and compelling evidence suggests an active participation of the endoc-
annabinoid system in the pathophysiology of this disease. The ubiquitous distribution of cannabinoid receptors, together with the
physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function further support
the therapeutic interest of cannabinoids for osteoarthritis. However, limited clinical evidence has been provided to support this
therapeutic use of cannabinoids, despite the promising preclinical data. This review summarizes the promising results that have
been recently obtained in support of the therapeutic value of cannabinoids for osteoarthritis management.

Osteoarthritis: clinical data
Incidence and relevance of the disease
Osteoarthritis is the most common form of arthritis or degenerative
joint disease. This disease results from damage to the articular carti-
lage induced by a complex interplay of genetic, metabolic, biochem-
ical and biomechanical factors followed by activation of
inflammatory responses involving the interaction of the cartilage,
subchondral bone and synovium (Haseeb & Haqqi, 2013). Osteoar-
thritis affects both men and women of all ethnic groups in all geo-
graphic locations, although it occurs more frequently in women. The
disease most commonly affects the middle-aged and elderly, even
though younger people may be affected mainly as a result of injury
or overuse. Age is the strongest predictor, and extended life expec-
tancy will result in a greater occurrence of the disease. However,
other systemic factors also play a major role in the aetiology of
osteoarthritis, such as genetics, diet, hormonal status and bone den-
sity, as well as local biomechanical factors including obesity, joint
injury and muscle weakness (Felson et al., 2000). It is estimated
that the number of people with osteoarthritis will have doubled by
2020 due to the rapidly increasing prevalence of obesity and the
elderly status. The World Health Organization estimates that 10% of
Correspondence: Dr R. Maldonado, as above.
E-mail: rafael.maldonado@upf.edu
*C.L.P. and S.A.B. contributed equally to this work.
Received 5 September 2013, revised 25 November 2013, accepted 2 December 2013
the world’s people over the age of 60 years suffer from osteoarthri-
tis, and that 80% of people with osteoarthritis have limitation of
movement (Buckwalter & Martin, 2006).
Most of the people with osteoarthritis seek medical attention
because of joint pain that is frequently localized around the knee
and distal femur (Buckwalter & Martin, 2006). The osteoarthritis
pain includes both nociceptive and non-nociceptive components, and
is associated with abnormally excitable pain pathways in the periph-
eral nervous system and CNS (Mease et al., 2011). Indeed, patients
with osteoarthritis have lower thresholds for mechanical and thermal
pain than healthy controls (Farrell et al., 2000), and increased sensi-
tivity to pressure, ischaemia and innocuous stimuli (Kosek & Orde-
berg, 2000). Most of the patients with osteoarthritis describe pain as
aching that may enhance with changes in the weather and increased
physical activity (Buckwalter & Martin, 2006). As joint degenera-
tion progresses, patients usually notice a gradual decrease in func-
tional movements, and difficulty in everyday simple tasks such as
walking, climbing stairs and housekeeping (Waldman, 2009). With
continued use, muscle wasting and adhesive capsulitis in the knee
may occur (Waldman, 2009). Besides physical disabilities, patients
with osteoarthritis may suffer sleep disturbance, anxiety, feelings of
helplessness or depression, which may impair the quality of life.
Functional magnetic resonance imaging studies have identified
several brain regions involved in osteoarthritis pain processing, indi-
cating the complexity of the mechanisms involved in this disease
(Sofat et al., 2011). Indeed, painful mechanical knee stimulation in
osteoarthritis was associated with bilateral activation of secondary
somatosensory, insular and cingulate cortices and thalamus, as well
as unilateral activation of the putamen and amygdala (Baliki et al.,

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
486 C. La Porta et al.
2008). In addition, positron emission tomography in patients with
osteoarthritis revealed bilateral activation of many brain areas
involved in pain processing, including the cingulate, prefrontal, or-
bitofrontal and primary somatosensory cortex (Kulkarni et al.,
2007).
Treatments available
Currently, therapeutic approaches for osteoarthritis are mainly symp-
tomatic with the purpose of reducing pain, and curative treatments
are not still available (Hunter, 2011). In addition, these therapies
have a modest efficacy in most of the cases, and leave patients with
considerable pain and a functional disability. The present manage-
ment of osteoarthritis includes pharmacological and non-pharmaco-
logical therapies. According to Osteoarthritis Research Society
International, this treatment is directed towards reducing joint pain
and stiffness, maintaining and improving joint mobility, reducing
physical disability and handicap, improving health-related quality of
life, limiting the progression of joint damage, and educating patients
about the nature of the disorder and its management (Zhang et al.,
2008).
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered
as first-line pharmacological therapy in patients with osteoarthritis
with mild to moderate pain (Lee et al., 2004). However, these com-
pounds have limitations, especially in elder populations because of
gastrointestinal side-effects, hepatic and renal toxicity. Patients who
do not respond or cannot tolerate NSAIDs and continue to have
severe pain may be considered candidates for opioid therapy. Never-
theless, tolerance, dependence and other adverse effects, including
constipation, may occur with opioid use. Topical NSAIDs and cap-
saicin can be effective as adjunctives and alternatives to systemic
administered analgesic agents in osteoarthritis. In addition, intra-
articular injections of corticosteroids have been beneficial especially
in treating acute pain episodes in patients not responding to oral
analgesics (Ravaud et al., 1999).
It is widely accepted that the optimal treatment for osteoarthritis
combines medication with non-pharmacological therapies. Non-phar-
macological interventions are frequently used in the management of
patients with osteoarthritis (Sarzi-Puttini et al., 2005), and are cur-
rently still considered the first-line treatment. Among these non-
pharmacological modalities, the most widely proposed include
weight reduction, education and self-management, physical therapy,
aerobics, muscle strengthening, walking aids, thermal modalities,
transcutaneous electrical nerve stimulation and acupuncture (Sarzi-
Puttini et al., 2005).
A new strategy for osteoarthritis drug development is focused on
modifying the structural progression of the disease. This approach
could cause retardation, a complete halt in disease progression, a
reverse in disease progression and even the prevention of disease
development (Hunter, 2011). Some disease-modifying osteoarthritis
drugs have shown promising results in clinical trials (see ‘Transla-
tional value of the animal studies’) and could represent new thera-
peutic approaches in the near future.
In patients with severe osteoarthritis that significantly limits their
activities and that does not respond to other treatments, surgery is
usually recommended. However, surgery is counselled before the
disease causes complications, such as muscle loss and joint deformi-
ties. Finally, biological restoration of the articular cartilage has also
been explored by stimulating resident hyaline cartilage, biologically
enhancing bone marrow progenitors, or by cartilage transplantation
(Buckwalter & Mankin, 1998; Sarzi-Puttini et al., 2005). Therefore,
osteoarthritis treatment remains an open issue to deal with, and there
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
is an urgent need for more effective drugs and new animal models
for better understanding the aetiology and pathophysiology of this
disease.
Animal models
Benefits and limitations of the existing animal models
The validity of an animal model is typically assessed by three main
criteria – face validity that refers to how closely key symptoms of
the human disorder are mimicked by the animal model; construct
validity defined by the similarity of the cellular and molecular pro-
cesses in the animal model and the human patient; and predictive
validity that refers to the success of a pharmacological treatment in
humans that has been shown to have similar pharmacological effects
in the animal model (van der Staay et al., 2009).
Animal models have been used for several decades to study
arthritis, and have contributed to better understand the mechanisms
of pathogenesis and to validate new targets for treatment (Vincent
et al., 2012; summarized in Table 1). Nevertheless, these animal
models have limitations, and there is a continuous refinement of
existing models and generation of new ones (Vincent et al., 2012).
Most of the limitations of these models are due to differences in
anatomy, functionality, dimensions, cartilage repair processes and
thickness in comparison with human joints (Lampropoulou-Adami-
dou et al., 2013). In addition, the lesions developed in osteoarthritis
animal models correspond to those found in humans only in a par-
ticular stage of the disease (Lampropoulou-Adamidou et al., 2013).
However, the use of these models presents important benefits
because they allow the control of environmental parameters, the
cause, the exact time of the disease onset, and permit the collection
of tissue samples at any stage of the pathology.
Two categories of osteoarthritis animal models have been exten-
sively used – the induced and the spontaneous models (Longo et al.,
2012; Lampropoulou-Adamidou et al., 2013). Osteoarthritis can be
induced by surgery or by intra-articular injection of chemical agents.
A first surgical procedure to induce osteoarthritis consists of damage
of the anterior cruciate ligament, which represents a key element for
the development of osteoarthritis in humans (Kim et al., 2011). The
anterior cruciate ligament transection model was first induced in
mature beagle dogs and is nowadays the most frequently used model
in this animal species (Lampropoulou-Adamidou et al., 2013). This
model has also been validated in rodents, such as rabbits, guinea
pigs, rats and mice in which the cartilage lesion and synovitis
develop much more rapidly than in dogs. Anterior cruciate ligament
transection induces anatomical and biochemical changes resembling
human osteoarthritis in both the cartilage and subchondral bone
(Lampropoulou-Adamidou et al., 2013). Meniscus injury is fre-
quently correlated to osteoarthritis. Currently animal models for
osteoarthritis that induce meniscal injury comprise partial or com-
plete meniscectomy, meniscal transection and meniscal destabiliza-
tion. These models were described in dogs and rodents (guinea pigs,
rabbits, rats and mice). These procedures induce lesions that are
morphologically similar to those observed in humans, but occur
much more rapidly, probably due to the inapparent perception of the
animal that it should not continue using the unstable joint, as would
be the case with most humans (Bendele, 2001). These models are
not appropriate for detecting possible protective effects of drugs due
to the rapid progression of cartilage degeneration (Bendele, 2001).
A significant association of low serum oestrogen and developing
knee osteoarthritis has been shown in postmenopausal women (Sow-
ers et al., 2006). To study this potential cause of osteoarthritis, an
European Journal of Neuroscience, 39, 485–500
 Cannabinoid system in osteoarthritis 487

Table 1. Animal models of osteoarthritis

Model Species References

Induced models
Surgical models
Anterior cruciate ligament Rats, mice, dogs, rabbits Reviewed by Moskowitz et al. (2007)
Transection Goats, sheep Reviewed by Lampropoulou-Adamidou et al. (2013)
Meniscus injury
Meniscal tear Dogs, guinea pigs, rats, mice Reviewed by Bendele (2001)
Partial menisectomy Reviewed by Lampropoulou-Adamidou et al. (2013)
Complete menisectomy Reviewed by Longo et al. (2012)
Ovariectomy Rats, guinea pigs, rabbits, mice, sheep Reviewed by Sniekers et al. (2008)
Chemical models
Monosodium iodoacetate Rats Fernihough et al. (2004); Sagar et al. (2010)
Mice Harvey & Dickenson (2009); La Porta et al. (2013)
Papain Rabbits Miyauchi et al. (1993)
Mice van der Kraan et al. (1989); van Osch et al. (1994)
Collagenase Mice van Lent et al. (2012)
Quinolone Mice Reviewed by Sendzik et al. (2009)
Immunotoxins Rats, mice Salo et al. (1997); Nagai et al. (2012)
Spontaneous models
Naturally occurring Guinea pigs, Syrian hamster Reviewed by Lampropoulou-Adamidou et al. (2013)
Dogs, non-human primates
Genetic models
STR/ort Mice Kyostio-Moore et al. (2011)
Overexpression of cathepsin K Mice Morko et al. (2005)
Postnatal expression of constitutively Mice Neuhold et al. (2001)
Active human collagenase-3
Del1 Mice Saamanen et al. (2000)

oestrogen deficiency by ovariectomy has been developed as an ani-
mal model. In rats, ovariectomy led to mild osteoarthritis lesions
characterized by accelerated cartilage turnover and increased carti-
lage surface erosion (Hoegh-Andersen et al., 2004). This procedure
was also described in other rodents, such as guinea pigs, rabbits,
mice as well as in primates, demonstrating the deleterious effects of
oestrogen deficit on articulate cartilage (Sniekers et al., 2008).
Focal trauma causing defects in the cartilage surface in humans is
repaired with tissue that is commonly inferior to the original carti-
lage, being a quite common cause of osteoarthritis. Articular groove
is another surgically induced model of osteoarthritis. In this model,
inferior repair tissue may subsequently lead to osteoarthritis (Ahern
et al., 2009), and the extent to which the new tissue resembles carti-
lage is determined by the species, age, size of the defect and its ana-
tomic location.
Besides the surgical models, chemically induced osteoarthritis
models are widely used to assess the therapeutic efficacy of potential
agents. They require less invasive procedures, are easy to implement
and permit the study of osteoarthritic lesions at different stages.
However, the most important limitation of these models is the
absence of correlation with the pathogenesis of human osteoarthritis
(Lampropoulou-Adamidou et al., 2013). Chemical models include
intra-articular injection of substances having deleterious effects on
joint physiology – inhibition of chondrocyte metabolism, such as
papain or sodium monoiodoacetate (MIA); damage of ligaments and
tendons, such as collagenase; or selective joint denervation with
immunotoxins (Longo et al., 2012).
Monoiodoacetate inhibits chondrocyte glycolysis (van der Kraan
et al., 1989), and produces cartilage degeneration and subchondral
bone alterations (Guingamp et al., 1997; Janusz et al., 2001). The
pain-related behaviour developed after a single injection of MIA has
been widely described in rats (Fernihough et al., 2004; Sagar et al.,
2010) and more recently in mice (Harvey & Dickenson, 2009; La
Porta et al., 2013). Intra-articular injection of MIA in rodents easily
reproduces osteoarthritis-like lesions and functional impairment simi-
lar to that observed in human disease. This model is particularly
useful for studying chondroprotective drugs (Guingamp et al.,
1997).
Intra-articular administration of papain, an enzyme that degrades
proteoglycans in cartilage, is a model of osteoarthritis in rodents
(mice, rats and rabbits). The effects of papain injection are dose
dependent (Miyauchi et al., 1993). Thus, low doses do not com-
pletely impair the repair processes (Miyauchi et al., 1993) and per-
mit the study of different stages of osteoarthritis progression. One of
the limitations of this model is that the resultant pathology probably
does not fully represent that of osteoarthritis as the injection is
accompanied by acute inflammatory reaction (Lampropoulou-Adami-
dou et al., 2013).
Collagenase-induced osteoarthritis is commonly used in mice
(Lampropoulou-Adamidou et al., 2013). Collagenase provokes joint
instability by degrading the structures containing collagen, such as
the joint capsule and ligament. Synovial activation is important for
the induction of joint pathology, and macrophages are the predomi-
nant cell type in the inflamed synovium of both humans and mice
with collagenase-induced osteoarthritis (van Lent et al., 2012).
Osteoarthritis can also be induced by the systemic administration of
quinolone antibiotics, which cause arthropathy and tendinopathy
when given in a growth period (Bendele, 2001).
A particular category of osteoarthritis models is represented by
the spontaneous ones. These models exhibit slow progression and
are time-consuming, but are closely related to human degenerative
osteoarthritis from the pathophysiological point of view (Lamprop-
oulou-Adamidou et al., 2013). Some laboratory animals such as
guinea pigs, Syrian hamsters, dogs and non-human primates can
spontaneously develop osteoarthritis, but the use of genetic models
has represented an important advance for the study of this disease.
Among the genetic models, the reduction in type II collagen sig-
nificantly contributes to the early-onset degeneration of knee joints

© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
European Journal of Neuroscience, 39, 485–500
488 C. La Porta et al.
in transgenic mice with mutations in cartilage collagen types II
and IX (Del1 mice; Saamanen et al., 2000). STR/ort mice, a
mouse strain that spontaneously develops osteoarthritis, exhibited
local and systemic pro-inflammatory conditions, both of which are
present in human osteoarthritis (Kyostio-Moore et al., 2011). Mice
overexpressing cathepsin K, an enzyme involved in bone remodel-
ling and resorption, present high bone turnover, osteopaenia and
develop osteoarthritis (Morko et al., 2005). Furthermore, postnatal
expression of constitutively active human collagenase-3 in hya-
line cartilage also induces osteoarthritis in mice (Neuhold et al.,
2001).
Most of the current animal models of osteoarthritis mimic the
symptoms of the human disorder, although no one completely repro-
duces the whole variety of signs and symptoms of human osteoar-
thritis, which represents an important limitation in terms of face
validity. Several available animal models of osteoarthritis present
some limitations in terms of construct validity. Indeed, the intra-
articular injection of chemical agents, such as MIA, papain or oth-
ers, alters the homeostasis and leads to the destruction of joint struc-
ture, although there is no correlation with the pathogenesis of any
kind of human osteoarthritis. In contrast, surgical and spontaneous
animal models of osteoarthritis have similar pathophysiological fea-
tures to human osteoarthritis related to post-traumatic and degenera-
tive disease. The predictive validity of osteoarthritis animal models
also has some limitations as the efficacy of drugs may not accurately
reflect those observed in human disease, when osteoarthritis progres-
sion occurs in the animal model much more rapidly, such as in
smaller species (Lampropoulou-Adamidou et al., 2013). Considering
these factors, the most appropriate animal model must always be
selected in the light of the specific aim of the study. Thus, studies
aimed at evaluating the pathogenesis of the disease may require the
use of naturally occurring models of osteoarthritis, while the use of
genetic models seems most appropriate in molecular studies. In
addition, the use of surgical models may be the most suitable for
studies aimed at investigating the therapeutic profile of specific com-
pounds, and the research into pain mechanisms related to osteoar-
thritis could rely upon chemical models (Lampropoulou-Adamidou
et al., 2013).
Despite the numerous animal models for osteoarthritis, a gold
standard model that can be truly defined to represent human aetiol-
ogy is still not available. Each model has distinct advantages and
disadvantages, and allows the knowledge of a small part of human
osteoarthritis in terms of natural history, mechanisms and symptoms.
Thus, more than one single animal model is usually required to
define the therapeutic efficacy of a potential treatment.
Translational value of the animal studies
The development of many potential agents for osteoarthritis is often
interrupted because of a lack of efficacy in the different animal
models available. In addition, the development of multiple com-
pounds that are efficacious in these preclinical models is also termi-
nated because of the difficulties in demonstrating the clinical
activity. Nevertheless, several compounds have been moved success-
fully into clinical stages of development.
Doxycycline, a potent matrix metalloproteinase inhibitor, slowed
the rate of joint space narrowing in knees with established osteoar-
thritis in a randomized, placebo-controlled, double-blind trial
(Brandt et al., 2005), which confirms the preclinical data suggesting
that doxycycline can slow the progression of osteoarthritis
(Yu et al., 1992). In contrast, another matrix metalloproteinase
inhibitor, PG-116800, revealed musculoskeletal toxicity in clinical
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
trials without clear benefit after administration in patients with knee
osteoarthritis (Krzeski et al., 2007).
Controversial data were also reported in clinical trials regarding
the efficacy of bisphosphonates in osteoarthritis in spite of their
efficacy in different animal models. Thus, risedronate improved
both joint structure and symptoms in patients with primary knee
osteoarthritis in a randomized, double-blind, placebo-controlled
1-year trial (Spector et al., 2005). In a 2-year multinational study,
risedronate decreased biochemical markers of cartilage degradation
in patients with knee osteoarthritis, but did not decrease symptoms
or slow radiographic progression (Bingham et al., 2006). Pralnaca-
san, a highly selective caspase-1 inhibitor that reduces the pro-
inflammatory cytokine interleukin (IL)-1b, involved in cartilage
degradation, reduced joint damage in two mouse models of osteoar-
thritis (Rudolphi et al., 2003). However, the clinical investigation
was put on hold following toxicology studies in dogs owing to the
detection of liver changes (Wieland et al., 2005). Another IL-1b
inhibitor, diacerein, revealed beneficial effects in several animal
models of osteoarthritis developed in sheep (Hwa et al., 2001),
dogs (Pelletier et al., 2003) and rodents (Bendele et al., 1996).
However, diacerein has shown modest efficacy (Dougados et al.,
2001; Shin et al., 2013) or no effects (Pham et al., 2004) in clinical
studies.
After successful demonstration of their efficacy in preclinical
studies, pharmaceutical companies advanced the cathepsin K
inhibitors into the clinical trials. Thus, an orally active cathepsin
K inhibitor, 462795, was tested at Phase I for the treatment of
post-menopausal osteoporosis and arthritis (NCT00411190), but no
follow up studies were conducted (Yasuda et al., 2005).
Fibroblast growth factors are a group of proteins involved in carti-
lage repair. Among them, BMP-7 and FGF-18 have been shown to
stimulate cartilage repair in sheep (Chubinskaya et al., 2007) and rat
(Moore et al., 2005) models of osteoarthritis, respectively. BMP-7
improved symptoms of knee osteoarthritis in a Phase I safety study
that was performed in participants with osteoarthritis (Hunter et al.,
2010). In addition, Phase II trials have been completed with BMP-7,
although the results have not yet been released (NIH number-
NCT01111045). At present, FGF-18 is also under Phase II
(NCT01689337), but results are not yet available.
Licofelone, a competitive inhibitor of cyclooxygenase and 5-lip-
oxygenase, has been shown to protect the joint from degeneration
(Raynauld et al., 2009). A Phase III trial showed that licofelone
significantly reduced knee cartilage loss compared with naproxen
(Raynauld et al., 2009). However, the lack of a placebo group is a
significant weakness of this study, and no certain conclusions can
be drawn (Raynauld et al., 2009).
Nitric oxide (NO) is thought to have an important role in the
increased inflammatory stage within the tissues associated with
osteoarthritis cartilage degeneration (Hunter, 2011). A selective
inducible NO synthase (iNOS) inhibitor, L-NIL, prevented the pro-
gression of the disease in a dog model of osteoarthritis (Pelletier
et al., 2000). Moreover, a 2-year randomized, double-blind,
placebo-controlled, multicentre study recently showed that the orally
selective iNOS inhibitor SD-6010 slowed progression of mild, but
not severe, osteoarthritis (Hellio le Graverand et al., 2013).
Although the effects of steroids have been shown to be protective
in animal models of osteoarthritis (Pelletier et al., 1995), triamcino-
lone showed no significant effect in joint space vs. placebo in a ran-
domized control trial (Raynauld et al., 2003). Another hormone,
calcitonin, has been studied extensively in vitro and in animal mod-
els, and it appears to have beneficial effects in bone and cartilage
(Karsdal et al., 2007). Calcitonin preserved cartilage volume in
European Journal of Neuroscience, 39, 485–500

humans, but had no effects on joint space narrowing (Karsdal et al.,
2010).
Degradation and loss of aggrecan, an integral part of extracellular
matrix in cartilage tissue, occur in osteoarthritis. Thus, among the
aggrecanases, ‘a disintegrin and metalloproteinase with thrombo-
spondin motifs’ (ADAMTS) family has been demonstrated to have
a pathological role in osteoarthritis in mice (Majumdar et al., 2007).
Indeed, the ADAMTS inhibitor AGG-523 reduced aggrecan frag-
ments in joint injury in a rat model of osteoarthritis (Chockalingam
et al., 2011). AGG-523 has completed a Phase I clinical trial,
although the results are not yet available (NCT00427687 and
NCT00454298).
Besides these classical therapeutic options, other non-conventional
drugs, such as tricyclic anti-depressants, anticonvulsants and seroto-
nin/norepinephrine re-uptake inhibitors, have been considered for
arthritis pain treatment in preclinical or clinical studies (van Laar
et al., 2012). Tricyclic anti-depressants have shown anti-nociceptive
and anti-arthritic effects in rodent models (Butler et al., 1985), and
provide significant pain relief in patients with rheumatoid arthritis
vs. placebo (Frank et al., 1988), but are associated with important
adverse effects. Serotonin/norepinephrine re-uptake inhibitors would
be better tolerated than tricyclic anti-depressants, but may be less
effective analgesics. The selective serotonin and norepinephrine
re-uptake inhibitor duloxetine showed a moderate analgesic effect in
osteoarthritic rats (Chandran et al., 2009), and recent clinical studies
reported that it was an effective and tolerable analgesic in patients
with knee osteoarthritis (Chappell et al., 2011; Micca et al., 2013).
Whereas anticonvulsants are known to be effective analgesics in
fibromyalgia and in preclinical models of osteoarthritis (Rahman
et al., 2009), these agents have not been studied in rheumatoid
arthritis or osteoarthritis populations (Moore et al., 2009).
Finally, nutritional supplements such as glucosamine, chondroitin
sulphate (Richy et al., 2003), avocado-soybean (Ernst, 2003) and
vitamin D (Lane et al., 1999) also have favourable effects on the
progression of osteoarthritis in several clinical trials, even though
the results are controversial. Glucosamine and chondroitin sulphate
are among the most commonly used dietary supplements for these
purposes. These compounds showed efficacy in reducing some
osteoarthritis symptoms in several randomized trials, although they
do not prevent the progression of the disease or regenerate damaged
cartilage (Akhtar & Haqqi, 2012). Avocado-soybean has been
shown to increase aggrecan synthesis, and to reduce catabolic and
pro-inflammatory mediator production by human osteoarthritic
chondrocytes (Henrotin et al., 2003). Studies of the effects of
avocado-soybean on osteoarthritis reported conflicting results with
respect to symptom modification (Davies et al., 2013).
A positive association between serum levels of 25-hydroxyvita-
min D and bone density has been found in patients with osteoarthri-
tis. Moreover, vitamin D supplementation for 2 years did not reduce
knee pain or cartilage volume loss in patients with symptomatic
knee osteoarthritis (McAlindon et al., 2013; NIH number –
NCT00306774).
Endocannabinoid system
In the last decade, a novel physiological system involved in the con-
trol of inflammatory and nociceptive responses, the endocannabinoid
system, has emerged as a potential target for the development of
new therapeutic strategies for pain treatment. The endocannabinoid
system has a particular interest in the development of new
treatments for osteoarthritis pain considering its physiological role
in the control of multiple responses that are important in the
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
European Journal of Neuroscience, 39, 485–500
Cannabinoid system in osteoarthritis 489
pathophysiology of this disease. Several preclinical studies have
confirmed the interest of specific targets within the endocannabinoid
system for the development of these novel therapeutic approaches.
The following sections of this review summarize the promising
results that have been recently obtained showing the interest of these
endocannabinoid targets for the treatment of osteoarthritis pain.
Cannabinoid receptors
The endocannabinoid system is composed of the cannabinoid recep-
tors, their endogenous ligands (endocannabinoids), and the enzymes
involved in the synthesis and degradation of these endocannabi-
noids. Cannabinoids exert their pharmacological effects through the
activation of at least two main cannabinoid receptors, the cannabi-
noid receptor 1 (CB1R) and 2 (CB2R). Both are G-protein-coupled
receptors with seven transmembrane domains associated with the
inhibitory Gi/o protein (Childers & Deadwyler, 1996). Nevertheless,
several evidences support the existence of other receptors that bind
cannabinoid ligands, such as GPR55 (Baker et al., 2006). The distri-
bution of the two cannabinoid receptors in the CNS and peripheral
tissues is rather different (Pertwee et al., 2010). CB1R is the most
abundantly expressed metabotropic receptor in the brain, and its dis-
tribution has been well characterized in rodents (Herkenham et al.,
1991; Tsou et al., 1998) and humans (Westlake et al., 1994). CB1R
is highly expressed in the hippocampus, basal ganglia, cortex and
cerebellum (Compton et al., 1990), and is less abundant in other
brain areas such as the telencephalon and diencephalon (Tsou et al.,
1998; Cota et al., 2003a). In all these areas, CB1R is mainly present
in glutamatergic and c-aminobutyric acid (GABA) neurons (Rodri-
guez et al., 2005). CB1R is also expressed in peripheral organs,
including adipocytes (Cota et al., 2003b), liver (Osei-Hyiaman
et al., 2006), lungs, smooth muscle, gastrointestinal tract (Calignano
et al., 1997), pancreatic cells (Bermudez-Silva et al., 2008), repro-
ductive organs (Gerard et al., 1991), immune system (Galiegue
et al., 1995), peripheral sensory nerves (Hohmann & Herkenham,
1999), sympathetic nerves (Ishac et al., 1996), chondrocytes (Mbv-
undula et al., 2006) and bone cells (Whyte et al., 2012).
CB2R is mainly expressed in the immune system cells, including
macrophages, neutrophils, monocytes, B-lymphocytes, T-lympho-
cytes and microglial cells (Munro et al., 1993; Galiegue et al.,
1995). Recently, CB2R expression has also been shown in skin
nerve fibres and keratinocytes (St€ander et al., 2005), bone cells
(Ofek et al., 2006), liver (Julien et al., 2005) and somatostatin-
secreting cells in the pancreas (Bermudez-Silva et al., 2008). The
presence of CB2R in primary sensory neurons and its role in the
regulation of nociceptor activity has been controversial. However,
several immunohistochemical and functional studies have demon-
strated the presence and role of CB2R in nociceptive control in
nerve fibres, including those innervating osteoarthritic synovium and
digit skin (St€ander et al., 2005; Anand et al., 2008). The presence
of CB2R has also been demonstrated in the CNS in astrocytes (San-
chez et al., 2001), microglial cells (Walter et al., 2003) and brain-
stem neurons (van Sickle et al., 2005). However, the functional
activity of CB2R in neurons remains a controversial issue.
Endocannabinoids
The most relevant endogenous ligands for cannabinoid receptors are
N-arachidonoyl-ethanolamine (anandamide or AEA) and 2-arachido-
noylglycerol (2-AG; Devane et al., 1992; Mechoulam et al., 1995).
These endocannabinoids are synthesized on demand, mainly post-
synaptically, and act as retrograde messengers regulating the release
490 C. La Porta et al.
of a variety of neurotransmitters at the presynaptic level (Wilson &
Nicoll, 2002). Both AEA and 2-AG are produced from cell mem-
brane lipids via different biosynthetic pathways. The synthesis of 2-
AG from diacylglycerol is mediated by diacylglycerol lipase, while
AEA is synthesized from the phosphatidylethanolamine by the
action of two enzymes – N-acyltransferase and phospholipase D (Di
Marzo et al., 1994). Anandamide is mainly degraded by fatty-acid
amide hydrolase (FAAH; Di Marzo et al., 1994), whereas 2-AG is
primarily metabolized by monoacylglycerol lipase (MAGL; Dinh
et al., 2002).
Physiological role
The endocannabinoid system is involved in an extensive variety of
physiological and pathophysiological processes. This system has a
low tonic activity under physiological conditions and it is mainly
activated in a phasic manner in order to maintain the homeostatic
equilibrium in the CNS and peripheral tissues (Bisogno & Di Mar-
zo, 2010). The endocannabinoid system plays an important role in
multiple aspects of the neural functions, including the control of
movement and motor coordination (Rodrıguez De Fonseca et al.,
2001), learning and memory (Kano et al., 2009), emotion and moti-
vation (Mechoulam & Parker, 2013), addictive-like behaviour
(Maldonado et al., 2011) and pain modulation (Guindon & Hoh-
mann, 2009), among others. This system interacts with multiple neu-
rotransmitters, such as acetylcholine, dopamine, GABA, histamine,
serotonin, glutamate, norepinephrine, prostaglandins and opioid pep-
tides (Dewey, 1986), and this interaction is responsible for most of
the neuronal effects of cannabinoids (Grotenhermen, 2004). At the
peripheral level, the endocannabinoid system modulates different
processes, such as metabolism and energy storage, immune
responses, bone remodelling, cardiovascular, respiratory, reproduc-
tive and gastrointestinal function, among others (Grotenhermen,
2005). Acting at both central and peripheral levels, the endocannabi-
noid system plays an important physiological role in the control of
nociceptive responses and the development of chronic pain manifes-
tations.
Recent findings suggest that the endocannabinoid system plays an
important role in the peripheral regulation of nociception (Agarwal
et al., 2007; Clapper et al., 2010). In agreement, CB1R present on
nociceptor terminals may mediate the anti-nociceptive and anti-
inflammatory actions of locally produced AEA through its inhibitory
influence on the release of excitatory neuropeptides (Clapper et al.,
2010). CB1R (Bridges et al., 2003; Agarwal et al., 2007) and
CB2R (St€ander et al., 2005; Anand et al., 2008) are also expressed
in the dorsal root ganglia, and their stimulation at this level also
decreases nociceptive transmission (Millns et al., 2001; Anand
et al., 2008). However, immune cells and keratinocytes are also
involved in the peripheral CB2R analgesia as CB2R activation
reduces the release of pro-nociceptive molecules from these cells
(Ibrahim et al., 2005).
At the central level, the endocannabinoid system controls nocicep-
tion through CB1R located at spinal and supraspinal levels (Meng
et al., 1998). This modulation has been well characterized at the
spinal level, where CB1R is mainly found in the dorsal horn,
although most of the primary afferent neurons that express CB1
mRNA are non-nociceptive large-diameter fibres (Hohmann & Her-
kenham, 1999). However, CB1R is also expressed in nociceptive
Ad and C fibres, and inhibits the release of neurotransmitters
involved in pain (Drew et al., 2000; Wilson & Nicoll, 2002). In
addition, CB2R has also been recently proposed to participate in
pain modulation in the spinal cord (Racz et al., 2008).
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
At the supraspinal level, CB1R stimulation inhibits pain transmis-
sion acting on the ascending pathways, mainly at the thalamus level
(Martin et al., 1999), and modifies the subjective interpretation of
pain by modulating neuronal activity in limbic structures, such as
amygdala (Manning et al., 2003). Another central mechanism for
CB1R anti-nociception is the modulation of the descending inhibi-
tory pathways. Microinjection of cannabinoid agonists into the peri-
aqueductal grey matter (Martin et al., 1999) and rostroventromedial
medulla (Martin et al., 1998), as well as the electrostimulation of
these areas (Fields et al., 1991), resulted in analgesia by a CB1R-
dependent mechanism. Cannabinoids stimulate the descending inhib-
itory pathway by activating neurons from both brain regions through
inhibition of GABA release in the axon terminal of presynaptic in-
terneurons (Rea et al., 2007). The possible involvement of CB2R in
the supraspinal control of pain remains an open issue.
The administration of endocannabinoids or exogenous cannabi-
noids produces anti-nociception in different acute pain models
(Guindon & Hohmann, 2009). These anti-nociceptive effects may
differ depending on the assay, the cannabinoid employed and/or the
mechanism used to modify endocannabinoid levels. The endocanna-
binoid uptake inhibition as well as the exogenous administration of
endocannabinoids (AEA and 2-AG) and the use of MAGL and
FAAH inhibitors produces anti-nociception in these different models
through CB1R activation. However, CB1R-independent mechanisms
also participate in AEA anti-nociception, and a potential role of
CB2R has also been reported in endocannabinoid anti-nociception
(Guindon & Hohmann, 2009).
The activation of the endocannabinoid system also produces anal-
gesic effects in chronic pain models. Cannabinoid agonists, endoc-
annabinoids and/or their modulators produce anti-nociceptive effects
in different inflammatory pain models (Guindon & Hohmann,
2009). Anti-nociception produced by AEA and endocannabinoid
uptake inhibitors in these models is mediated by CB1R, whereas
2-AG predominantly produces CB2R-mediated anti-nociception
(Guindon & Hohmann, 2009). CB1R and CB2R activation also pro-
duces anti-nociception in neuropathic pain models (Guindon & Hoh-
mann, 2009). An upregulation of spinal CB1R was revealed after
sciatic nerve injury that promotes the enhancement of cannabinoid
analgesic effects on neuropathic pain in rodents (Lim et al., 2003).
In addition, CB2R expression was induced in the spinal cord during
neuropathic pain (Zhang et al., 2003), and CB2R has also been
involved in the development of neuropathic pain (Racz et al., 2008).
Moreover, the pharmacological modulation of endocannabinoid lev-
els by administration of endocannabinoids and/or FAAH/MAGL
inhibitors suppresses neuropathic pain in rodents (Hohmann, 2002).
In different models of bone cancer, CB1R and CB2R activation pro-
duce anti-nociception and reduce bone loss (Lozano-Ondoua et al.,
2010). AEA administration also reduces hyperalgesia in a model of
bone cancer pain through CB1R activation (Khasabova et al.,
2008). Nevertheless, intrathecal administrations of FAAH or MAGL
inhibitors did not produce anti-nociception in these cancer models
(Furuse et al., 2009). The activation of the endocannabinoid system
has been revealed to be of particular interest for the treatment of
osteoarthritis and joint pain, as described in the next sections.
Endocannabinoid system and osteoarthritis
The major clinical outcome of osteoarthritis is a complex pain state
that includes manifestations of both nociceptive and neuropathic
mechanisms. Several findings support the interest of the endocanna-
binoid system as an emerging therapeutic option for osteoarthritis.
Indeed, recent studies have demonstrated the anti-nociceptive effects
European Journal of Neuroscience, 39, 485–500

of both CB1R and CB2R agonists in rodent models of osteoarthritis
(Schuelert & McDougall, 2008; Yao et al., 2008). In agreement,
knee joints possess an active endocannabinoid system (Schuelert &
McDougall, 2008; Schuelert et al., 2011) that contributes to the reg-
ulation of synovial blood flow and joint pain (McDougall et al.,
2008; Schuelert & McDougall, 2008; Schuelert et al., 2010). More-
over, the putative presence of cannabinoid receptors on chondro-
cytes (Mbvundula et al., 2006) and bone (Idris & Ralston, 2012)
suggests a possible role of cannabinoids in regulating cartilage
breakdown and bone remodelling processes that take place during
osteoarthritis.
Pathophysiological role of the endocannabinoid system in
osteoarthritis
Compelling evidence suggests an active participation of the endoc-
annabinoid system in the pathophysiology of joint pain associated
with osteoarthritis. Thus, a functional role of CB1R and CB2R was
demonstrated in joint tissues of rodents (Schuelert & McDougall,
2008; Schuelert et al., 2010) and humans (Richardson et al., 2008).
Furthermore, pharmacological studies have suggested a peripheral
endocannabinoid tone that modulates nociceptor activity in osteoar-
thritic joints (Schuelert & McDougall, 2008; see next section). The
main elements of the endocannabinoid signalling system, including
CB1R and CB2R mRNA and protein, were found in synovial biop-
sies deriving from total knee arthroplasty of advanced osteoarthritis
and rheumatoid arthritis patients (Richardson et al., 2008). Both
AEA and 2-AG were detected in the synovial fluid of these patients,
but not in healthy volunteers, providing further evidence for a func-
tional endocannabinoid system in osteoarthritic joints (Richardson
et al., 2008). Spinal cord levels of AEA, 2-AG and their synthesiz-
ing enzymes were also increased in the rat MIA model of osteoar-
thritis (Sagar et al., 2010). These elevated endocannabinoid levels
modulate the excitability of spinal neurons in osteoarthritic rats
through both CB1R and CB2R (Sagar et al., 2010). Similarly, a
downregulation of CB1R and CB2R gene expression was recently
shown in the ipsilateral lumbar spinal cord of mice after MIA injec-
tion that would be probably promoted by the increased spinal endoc-
annabinoid tone in this model (La Porta et al., 2013). Adaptive
modifications induced by MIA at the spinal level were also revealed
in the endogenous opioid system (La Porta et al., 2013) that is in
close relationship with the endocannabinoid system in the control of
pain (Maldonado & Valverde, 2003). All these findings provide
Table 2. Pharmacological modulation of osteoarthritis and inflammatory arthritis by cannabinoids
Administration
Drug route Effect
ACEA Local Reduction of afferent fibres hypersensitivity
GW405833 Local Sensitization of joint mechanoreceptors
Increase of hindlimb incapacitance
A-796260 Systemic Reduction of nociception
URB597 Local or Reduction of nociception
systemic
Reduction of spontaneous activity of joint afferents
Cannabidiol Systemic Immunosuppressive, anti-inflammatory, anti-arthritic effects
HU-320 Systemic Immunosuppressive, anti-inflammatory, anti-arthritic effects
Ajulemic acid Systemic Anti-arthritic effect
Sch.036 Systemic Bone loss inhibition, modest reduction
of inflammation, reduction of leukocyte trafficking
ACEA, arachidonyl-2-chloroethylamide; MIA, sodium monoiodoacetate.
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
European Journal of Neuroscience, 39, 485–500
Cannabinoid system in osteoarthritis 491
evidence for both peripheral and central adaptive changes involving
the endocannabinoid system during osteoarthritis.
A crucial role of CB2R in the development of osteoarthritis pain
has been recently demonstrated by using genetically modified mice
(La Porta et al., 2013). Indeed, mechanical allodynia induced by
MIA was exacerbated in CB2R knockout mice, as revealed by a
mirror pain image in the non-injured paw. These manifestations
were attenuated in transgenic mice overexpressing CB2R in the
CNS, which reveals the important role of central mechanisms in the
control of these nociceptive responses (La Porta et al., 2013). By
contrast, no alterations in these nociceptive responses were revealed
in CB1R knockout mice, suggesting that this receptor does not play
a major role in this pain state (La Porta et al., 2013). These
behavioural data did not correlate with the degree of the histological
alterations in the knee joints, but correlated well with the adaptive
changes in the gene expression of cannabinoid receptors in the lum-
bar spinal cord, confirming the functional relevance of these central
changes involving the endocannabinoid system (La Porta et al.,
2013). Similar evidences about the relevance of an endogenous
CB2R tone were previously reported in a model of neuropathic pain
using the same lines of genetically modified mice (Racz et al.,
2008). In contrast, the endogenous CB1R tone was not crucial for
the development of neuropathic pain (Casta~ ne et al., 2006). How-
ever, a conditional genetic disruption of CB1R in peripheral noci-
ceptors has been reported to modify neuropathic pain manifestations
and to reduce the analgesic effects of cannabinoids in a neuropathic
pain model, suggesting that peripheral CB1R constitutes an impor-
tant target for cannabinoid-induced analgesia (Agarwal et al., 2007).
Pharmacological modulation of osteoarthritis pain by
cannabinoids
Recent behavioural and electrophysiological studies have demon-
strated that cannabinoids exert anti-nociceptive effects in rodent
models of osteoarthritis (Schuelert & McDougall, 2008; Yao et al.,
2008; Table 2). The local administration of the CB1R agonist,
arachidonyl-2-chloroethylamide (ACEA), into the knee joint reduced
the hypersensitivity of afferent nociceptors in the rat MIA model by
a mechanism involving CB1R and transient receptor potential vanil-
loid-1 (TRPV-1) channel (Schuelert & McDougall, 2008). Interest-
ingly, ACEA anti-nociception was greater in the osteoarthritis joints
compared with control joints (Schuelert & McDougall, 2008). In
addition, the intra-articular application of a CB1R antagonist alone
Model References
MIA Schuelert & McDougall
(2008)
MIA Schuelert et al. (2010)
MIA Yao et al. (2008)
MIA Schuelert et al. (2011)
Aged guinea pigs
Aged guinea pigs
Collagen-induced arthritis Malfait et al. (2000)
Collagen-induced arthritis Sumariwalla et al. (2004)
Adjuvant-induced arthritis Zurier et al. (1998)
Antigen-induced arthritis Lunn et al. (2007)
492 C. La Porta et al.
increased the activity of afferent nerve fibres in the osteoarthritic
joint, but not in the control joint, suggesting a tonic release of en-
docannabinoids at the joint level during osteoarthritis (Schuelert &
McDougall, 2008). Surprisingly, the local administration of a selec-
tive CB2R agonist, GW405833, produced a paradoxical sensitizing
effect on joint mechanoreceptors and increased hindlimb incapaci-
tance in osteoarthritic rats, but not in control rats (Schuelert et al.,
2010). This effect was mediated by the interaction of GW405833
with TRPV-1 on type IV joint afferents, where it co-localizes with
CB2R (Schuelert et al., 2010). In contrast, the systemic administra-
tion of the CB2R agonist, A-796260, showed a dose-dependent
analgesic activity in the rat MIA model (Yao et al., 2008). Simi-
larly, the systemic administration of the CB2R agonist JWH133
attenuated pain in the rat MIA model and reversed the changes in
circulating pro- and anti-inflammatory cytokines (Chapman, 2013).
The distinct results obtained with these CB2R agonists could depend
on the route of administration as the systemic route may produce
analgesic effects through spinal and supra-spinal mechanisms.
The possibility of alleviating pain by targeting the degradation
pathways of endocannabinoids (Guindon & Hohmann, 2009;
Roques et al., 2012) was also tested in animal models of osteoar-
thritis. Systemic or local administration of the FAAH inhibitor
URB597 reduced nociception in spontaneous and chemically
induced models of osteoarthritis, an effect blocked by CB1R, but
not CB2R, antagonism (Schuelert et al., 2011). Importantly,
URB597 had no effect on control rat joints, suggesting a release of
articular endocannabinoids only in osteoarthritic animals. URB597
also reduced the spontaneous activity of knee joint afferents in aged
osteoarthritic guinea pigs, reflecting the abrogation of osteoarthritis
pain at rest (Schuelert et al., 2011). Pain at rest is one of the main
debilitating and treatment-resistant symptoms of osteoarthritis, and
FAAH inhibition could offer an innovative strategy to treat this
aspect of pain (Schuelert et al., 2011), although it has not been con-
firmed in a recent clinical trial with osteoarthritic patients (Huggins
et al., 2012; see the following sections). Therefore, although the
potential utility of CB2R agonists in osteoarthritis pain requires
additional investigation, targeting the endocannabinoid-metabolizing
enzymes or CB1R at the peripheral level may represent an important
therapeutic approach to alleviate osteoarthritis pain.
Osteoarthritis pain has neuropathic and inflammatory components,
and those cannabinoids that exert a beneficial effect in neuropathic
and inflammatory pain states (Pertwee, 2012) would also be favour-
able for this specific pain state. Proof of a possible neuropathic com-
ponent participating in osteoarthritis pain comes from the
observation of a temporal expression of a biomarker of nerve dam-
age/neuropathy, ATF-3 protein, in the rat MIA model (Ivanavicius
et al., 2007; Orita et al., 2011), and the appearance of signs of trun-
cated nerves in the healing joint after joint injury (McDougall et al.,
1997). The inflammatory component in osteoarthritis is more vari-
able than in other non-degenerative forms of arthritis, such as rheu-
matoid arthritis. Variable degree of synovial hypertrophy and
synovial effusions, subchondral bone marrow oedema and the pres-
ence of inflammatory cells in the sub-lining tissues are some of the
pathological findings suggesting that osteoarthritis pain could also
be evoked by recurring inflammatory episodes (Schaible et al.,
2009). Cannabinoids exert both immunosuppressive and anti-inflam-
matory actions by mechanisms that include effects on apoptosis,
inflammatory cell proliferation and trafficking, cytokine production
and regulatory T-cells (Rieder et al., 2010). In agreement, the
non-psychoactive cannabis constituent cannabidiol (Malfait et al.,
2000) and the synthetic non-psychoactive cannabinoid acid HU-320
(Sumariwalla et al., 2004) showed immunosuppressive, anti-inflamma-
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
tory and anti-arthritic effects in the murine collagen-induced arthri-
tis. In addition, ajulemic acid, a synthetic derivative of D9-
tetrahydrocannabinol (THC), reduced the severity of adjuvant-
induced arthritis (Zurier et al., 1998, 2003) by a mechanism involv-
ing the peroxisome proliferator-activated receptor-c (Liu et al.,
2003). The precise role of cannabinoid receptors in the modulation
of the anti-inflammatory activity of cannabinoids in these experi-
mental models of arthritis has not been fully elucidated. Neverthe-
less, the CB2R antagonist/inverse agonist, Sch.036, inhibited bone
loss and reduced inflammation and leukocyte trafficking in a rat
model of antigen-induced arthritis (Lunn et al., 2007). Although
these cannabinoid compounds displayed anti-arthritic effects in these
chronic inflammatory arthritis models, their potential effects on pain
and structural pathology in specific models of degenerative arthritis
have not been yet evaluated. However, targeting peripheral CB1R or
CB2R would represent a new strategy for osteoarthritis treatment.
Accordingly, the peripheral administration of the CB1R agonist
ACEA produced anti-nociception in the rat model of osteoarthritis
pain (Schuelert & McDougall, 2008). Although several data support
a functional role of CB2R in chronic joint pain (Yao et al., 2008;
Sagar et al., 2010; La Porta et al., 2013), more studies are necessary
to evaluate the potential benefits of CB2R agonists for osteoarthritis.
Potential effects of cannabinoids on the progression of
osteoarthritis
Recent research on the molecular pathways involved in progressive
joint destruction has revealed the great complexity of osteoarthritis
pathogenesis. A growing body of evidence has highlighted the rele-
vance to focus on cartilage and bone as a unique functional unit, in
the attempt to identify therapeutic agents able to modify the course
of the disease (Lories & Luyten, 2011). The presence of local joint
inflammation and altered cartilage and bone turnover in osteoarthritis
implicates a great variety of pain mechanisms that can be influenced
by non-cartilaginous structures in the joint (synovium and bone), as
the cartilage is an avascular and aneural tissue (Sofat et al., 2011).
Cannabinoids exert a direct effect on chondrocytes, synovium and
bone metabolism, which reveals an attractive therapeutic potential.
Synthetic cannabinoids showed protective effects toward cytokine-
induced extracellular matrix degradation in cartilage through the
inhibition of the synthesizing enzymes of inflammatory mediators,
such as prostaglandin E2 (PGE2) and NO (Mbvundula et al., 2005,
2006). Excessive PGE2 and NO production are involved in the aeti-
opathogenesis of osteoarthritis (Henrotin et al., 2003; Martel-Pelle-
tier et al., 2003). Therefore, cannabinoids could have a modulatory
effect on the early stages and progression of osteoarthritis disease.
An innovative approach for articular cartilage defects consists of
the implantation of hydrogel scaffold containing platelet-rich plasma
with autologous chondrocytes, as revealed in a rabbit model of
micro-fractures (Lee et al., 2012). Interestingly, this implantation
system enhances chondrogenic maturation and differentiation, and
may have direct protective properties on cartilage remodelling by
upregulating the expression of CB1R and CB2R (Lee et al., 2012).
Cannabinoids also have effects on fibroblast-like synovial cells, the
stromal cells of the joint capsule that during arthritic disorders
express a hyperplastic, inflammatory, cartilage- and bone-destructive
phenotype, including secretion of cytokines and matrix metallopro-
teinases (Aupperle et al., 1998). Thus, synthetic cannabinoids,
CP55,940 and WIN55,212-2, reduced the levels of IL-6 and IL-8
released by IL-1b-stimulated fibroblast-like synoviocytes obtained
from patients with rheumatoid arthritis (Selvi et al., 2008). In addi-
tion, the ability of ajulemic acid, a cannabinoid agonist, to reduce
European Journal of Neuroscience, 39, 485–500

the severity of adjuvant-induced arthritis (Zurier et al., 1998, 2003)
seems to be partially mediated by an inhibitory effect on the produc-
tion of matrix metalloproteinases (Johnson et al., 2007). The mecha-
nisms by which cannabinoids exert these effects do not seem to be
completely mediated by CB1R or CB2R expressed in synovial cells.
The stimulation of the fibroblast-like synovial cells from osteoar-
thritis and rheumatoid arthritis patients with the CB1R/CB2R ago-
nist HU210 produced a time-dependent phosphorylation of the
extracellular signal-regulated kinases, suggesting the presence of
cannabinoid receptor activity in these cells (Richardson et al.,
2008). This phosphorylation was blocked more efficiently by CB1R
antagonism than by CB2R antagonism (Richardson et al., 2008).
The presence of endocannabinoids was also reported in the synovia
of these patients, together with an active FAAH (Richardson et al.,
2008). In addition, high endocannabinoid levels would participate in
the adhesion of synovial fibroblasts induced by glucocorticoids in vi-
tro by a mechanism dependent on CB1R/CB2R/TRPV-1 activation
(Lowin et al., 2012). This effect might decrease the migratory
potential of these cells and reduce cartilage destruction, underlining
the interest to target the endogenous cannabinoids for arthritis treat-
ment (Lowin et al., 2012).
The endocannabinoid system is also involved in bone metabolism
by regulating bone mass, bone loss and bone cell functions,
although the mechanisms by which endocannabinoids exert these
effects are still not fully understood (Idris & Ralston, 2012). How-
ever, the endocannabinoid system could also participate in regulat-
ing the excessive turnover of the subchondral bone observed in
patients and animal models of osteoarthritis (Kwan Tat et al., 2010).
All these in vitro studies reveal promising data about a potential role
of cannabinoids in the modulation of the mechanisms underlying the
structural pathology during osteoarthritis. However, further studies
exploring the overall in vivo effects of these agents in preclinical
models are necessary to support the potential interest of cannabi-
noids for avoiding the progression of osteoarthritis.
Clinical implications for cannabinoids in osteoarthritis
The use of cannabinoid agonists as therapeutic agents has mostly
remained outside traditional medicine despite their recognized
effects on pain and inflammation, due to their psychotropic side-
effects and the prejudice generated by the recreational use of mari-
juana. Nevertheless, the need for effective pain management has
focused the research on innovative therapeutic agents, among which
cannabinoids may deserve critical appraisal. Almost 10% of patients
with chronic pain in the USA are taking cannabinoids for self-medi-
cation purposes (Bronstein et al., 2011; Fitzcharles et al., 2012).
However, limited clinical evidence is available to fully support the
medical use of cannabinoids in osteoarthritis.
In the last few years, several drugs have been approved and mar-
keted for the treatment of osteoarthritis, whereas no approved dis-
ease-modifying osteoarthritis drugs are currently available. The
current clinical trials involve molecules that target pathogenic path-
ways, including inflammatory cytokines and related signalling path-
ways, proteases and NO inhibitors, agents regulating cartilage repair
and bone formation, as well as dietary supplements (see ‘Transla-
tional value of the animal studies’). The great hopes initially gener-
ated by most of the preclinical data gave disappointing results in
multiple clinical trials due to the appearance of side-effects or lack
of efficacy (Pulsatelli et al., 2013). One of the reasons for these neg-
ative results could be that the same molecular pathways involved in
osteoarthritis-related joint changes targeted for therapeutic manipula-
tion are also relevant for the physiology of joint tissues.
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
European Journal of Neuroscience, 39, 485–500
Cannabinoid system in osteoarthritis 493
Drugs targeting the endocannabinoid system would offer the
advantage of providing a more selective control of pain pathways.
The strategy of preserving endocannabinoids by the inhibition of
their catabolic enzymes would promote endocannabinoid signalling
predominantly at the site of noxious stimulation, in which their syn-
thesis is upregulated. An efficient randomized, placebo-controlled
clinical trial was conducted with the irreversible FAAH1 inhibitor,
PF-04457845, in patients with knee osteoarthritis (Huggins et al.,
2012). PF-04457845 showed an excellent tolerability profile (Li
et al., 2012) and strongly elevated the plasma levels of AEA and
other N-acylethanolamines, but failed to elicit effective analgesia in
these patients (Huggins et al., 2012), despite the analgesic properties
of FAAH inhibition in rodent models of osteoarthritis pain (Ahn
et al., 2011; Schuelert et al., 2011). The lack of analgesic effects in
this clinical trial was disappointing and suggested translational ques-
tions regarding animal models. Indeed, the great complexity of the
human disease would make the extrapolation of some preclinical
studies difficult, which must be taken into consideration when facing
this negative result. This result was not due to a problem in the trial
design as the positive control naproxen revealed robust effects. The
efficacy of FAAH inhibitor to reduce pain might depend on how
much FAAH activity contributes to the pathophysiology of human
osteoarthritis. Moreover, FAAH inhibitors may affect downstream
targets in different manners between species. Thus, the inhibition of
FAAH activity might have unmasked alternative pathways of AEA
and N-acylethanolamines in humans, such as the activation of
TRPV-1, which is associated with inflammatory processes, and their
breakdown via COX-2, that could have reduced the effects of ele-
vated AEA levels on pain (Di Marzo, 2012; Huggins et al., 2012).
The effects of this FAAH inhibitor on the level of inflammatory
cytokines and pain mediators, which could be differentially modu-
lated between species, also remained unexplored in this clinical trial.
Another point to be taken into consideration is that pain evaluation
in patients involves more subjective and emotional components than
preclinical assessment. Indeed, the authors raised the possibility that
the affective component of pain may have contributed to the lack of
efficacy of PF-04457845, based on previous observations that the
patient should be more anxious than those in the present trial to
obtain analgesia (Huggins et al., 2012). Other inhibitors need to be
considered in future studies as such a pharmacological approach
offers a major advantage over other classical analgesics, which tend
to target the entire pain pathway in a non-specific manner. It will be
important in future trials with FAAH inhibitors to correlate the
responses in patients with individual baseline FAAH levels, to eval-
uate additional biomarkers, and to consider their co-administration
with other drugs, such as COX-2 inhibitors, or dual FAAH/TRPV-1
blockers (Di Marzo, 2012; Huggins et al., 2012).
Information regarding the use of cannabinoids for the manage-
ment of pain in rheumatic conditions is available from anecdotal
reports, population surveys and a few clinical trials conducted in
patients with rheumatoid arthritis or fibromyalgia (Fitzcharles et al.,
2012). Recent systematic reviews have examined the effects of
cannabinoids for the treatment of chronic non-cancer-related pain
that include neuropathic pain, rheumatoid arthritis, fibromyalgia and
mixed chronic pain (Martin-Sanchez et al., 2009; Lynch & Camp-
bell, 2011). Among the different forms of cannabinoids that have
been considered, there were smoked cannabis, pharmacological can-
nabinoid preparations, such as dronabinol (Marinolâ), a stereoisomer
of THC, the synthetic analogue of THC, nabilone (Cesametâ), a
combination containing THC and cannabidiol named nabixomol
(Sativexâ), and novel THC analogues (ajulemic acid). The analgesic
effects of cannabinoids were superior to placebo in these different
494 C. La Porta et al.
pain conditions, although the therapeutic responses must be balanced
with adverse effects mainly on cognition, cardiovascular and motor
functions. However, these adverse effects were generally well toler-
ated (Lynch & Campbell, 2011). Particularly, the clinical trial car-
ried out with the oromucosal spray nabixomol (Sativexâ) resulted in
significant improvement in pain score and suppression of disease
activity in patients with rheumatoid arthritis without serious adverse
events (Blake et al., 2006). However, THC or nabilone produced
only a moderate effect in patients with fibromyalgia (Martin-Sanchez
et al., 2009; Lynch & Campbell, 2011; Fitzcharles et al., 2012).
Taken together, these studies demonstrated that cannabinoids repre-
sent modestly effective and safe treatment options for chronic non-
cancer pain. A recent follow-up study demonstrated that the long-
term use of Sativexâ was an efficacious treatment for pain relief in
patients with terminal cancer-related pain that was refractory to
strong opioid analgesics (Johnson et al., 2012). In agreement, Sati-
vexâ was accepted in Canada for the symptomatic relief of neuro-
pathic pain in multiple sclerosis and as an adjunctive analgesic
treatment for adult patients with advanced cancer (Pertwee, 2012).
However, further clinical studies with larger sample sizes and longer
duration are required to evaluate the efficacy and safety of cannabi-
noid compounds for pain treatment.
The present evidence of cannabinoid-induced analgesia in differ-
ent pain states, including inflammatory arthritis, offers opportunities
for cannabinoid therapeutic use in osteoarthritis pain as well. How-
ever, none of the clinical studies evaluating the effects of cannabi-
noids involved patients with osteoarthritis, revealing the need for
detailed clinical research about the possibilities of cannabinoid treat-
ment in osteoarthritis. Moreover, the narrow therapeutic window of
the currently available cannabinoid treatments unveils the need to
develop novel compounds for an efficient manipulation of the en-
docannabinoid systems in specific pain conditions.
Future perspectives for research in osteoarthritis
The continuous progress in the understanding of the molecular
mechanisms involved in osteoarthritis pathogenesis has revealed an
increasing number of potential targets for its effective treatment.
However, osteoarthritis treatment remains clinically challenging
because of the multiple mechanisms involved, the presence of co-
morbidities and the great heterogeneity of patient populations due to
differences in the degree of tissues pathology, the rate of progres-
sion, the severity of symptoms, the initiating causes, the gender and
the particular joint affected (van Laar et al., 2012). Multiple patho-
logical mechanisms involving all the joint tissues (cartilage, bone,
synovium and adjacent soft tissues) contribute to the complex clini-
cal presentation of osteoarthritis and complicate the identification of
efficient therapeutic interventions. This represents a major problem
that reveals the need to improve the preclinical research in both in
vitro and in vivo settings. Indeed, animal models currently available
in preclinical studies still lack the tissue and disease specificity of
prototypical patient populations. Although no single animal models
replicate human osteoarthritis conditions, each model can contribute
to clarify specific elements of the disease and provide information
that could be globally applicable.
Several concerns of translational value also arise from the pre-
clinical procedures commonly used for pain evaluation. Most of the
outcome measures of pain in animal models of osteoarthritis include
changes in locomotion, limb incapacitance, mechanical allodynia
and hyperalgesia, and spontaneous and evoked joint afferent nerve
activity. However, none of these different outcomes provides a
direct measure of spontaneous pain or pain at the joint level, like
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
that commonly experienced by patients. Indeed, allodynia is usually
evaluated in body regions distal from the affected joints, which
does not represent the principal symptomatic outcome in patients.
Moreover, differences in the response to specific analgesics were
often noted in different animal models, suggesting the presence of
distinct nociceptive mechanisms in each particular model of joint
disease (Little & Zaki, 2012). Therefore, the use of multiple osteo-
arthritis models would be consistent with the concept of disease
stratification, and would implicate a more adequate and precise
translation of the data to specific subpopulations of patients with
osteoarthritis (Little & Zaki, 2012). The existing limitations argue
for the need of continuous improvement in preclinical models and
revised strategies in osteoarthritis pain research (Hunter, 2011; Little
& Zaki, 2012).
Future perspectives for therapeutic use of cannabinoids
in osteoarthritis
Increasing evidence from preclinical studies supports the interest in
the endocannabinoid system as an emerging therapeutic target for
pain associated with osteoarthritis due to the ubiquitous distribution
of cannabinoid receptors and the effects of cannabinoids in the regu-
lation of pain, inflammation and even joint function. However, lim-
ited clinical evidence has been provided to support this therapeutic
use of cannabinoids. Extrapolations from the clinical trials that have
evaluated the effects of cannabinoids in other chronic pain condi-
tions, especially neuropathic pain and rheumatoid arthritis, raise sev-
eral questions concerning the real clinical efficacy and the risks
associated with long-term use. Indeed, medicinal cannabinoids are
associated with more adverse events in short-term trials, as com-
pared with placebo, including dizziness, disorientation, euphoria,
drowsiness and some cognitive alterations (Wang et al., 2008).
Long-term risks of therapeutic cannabinoid use on psychological
health, memory and cognition, development of dependence and
abuse, as well as interaction with other drugs are currently
unknown. Appropriate and well-controlled clinical trials with canna-
binoids would be required to clarify these important issues. In the
meantime, the preclinical research can also provide further convinc-
ing evidence to promote the therapeutic use of cannabinoids and
obtain agents with appropriate analgesic and safety profiles.
Most of the cannabinoids available for medical purpose are natu-
ral products of the Cannabis sativa plant, mostly accessed illegally
and without control regarding content or dosing. However, the phar-
maceutical companies have shown in recent years a growing interest
in the development of novel drugs that target cannabinoid receptors
or other components of the endocannabinoid system for therapeutic
intervention (Pertwee, 2009). These novel formulations include
peripheral restricted CB1R agonists that do not cross the blood–
brain barrier, selective CB2 agonists and specific modulators of the
endocannabinoid activity. Promising results have already been
obtained since targeting peripheral CB1R, as well as selective CB2R
agonism or the inhibition of FAAH activity have produced analgesic
effects in animal models of osteoarthritis (see previous sections).
Moreover, several findings support a crucial functional role
of CB2R in the regulation of chronic joint pain (Yao et al., 2008;
Sagar et al., 2010; La Porta et al., 2013), further supporting the
potential interest of CB2R agonists. Additional evidence supporting
the therapeutic value of cannabinoids for osteoarthritis management
comes from studies showing the beneficial effects of cannabidiol
and related compounds on inflammatory arthritis, although the
substantial differences in the mechanisms underlying inflammatory
and degenerative arthritis limit the direct extrapolation of the results.
European Journal of Neuroscience, 39, 485–500

In spite of the large preclinical evidence suggesting that the phar-
macological modulation of the endocannabinoid system would be of
interest for osteoarthritis, only one clinical trial targeted the endoc-
annabinoid system for symptomatic treatment. However, the lack of
analgesic effects of a FAAH inhibitor in patients with osteoarthritis
was revealed in this clinical trial, as mentioned above (Huggins
et al., 2012). This result has introduced unexpected complexities
suggesting that a better understanding of the pathophysiological role
of the endocannabinoid system is required to design successful treat-
ment strategies. A better knowledge of the signalling pathways
mediating the analgesic effects of CB1R and CB2R agonists in ani-
mal models of osteoarthritis would also be useful to define the
molecular mechanisms used by these receptors to regulate joint
pain.
An intriguing question that has not yet been addressed is to deter-
mine whether the therapeutic use of cannabinoids could be associ-
ated with abuse liability. The recently developed operant models of
‘self-medication’ in rodents can provide important information to
predict this possible risk in preclinical models (Gutierrez et al.,
2011; Bura et al., 2013). This innovative drug self-administration
paradigm in rodents exposed to chronic pain allows the identifica-
tion of safe and effective analgesics with limited abuse liability.
Indeed, a putative non-psychotropic analgesic may become reinforc-
ing under a specific pain state in these operant models due to its
ability to attenuate pain. Therefore, the possible abuse liability of a
putative analgesic compound can be determined by evaluating drug
self-administration in control sham animals not exposed to chronic
pain (Bura et al., 2013). This model also allows identifying drugs
that suppress spontaneous pain, which cannot be evaluated by the
traditional assessment of evoked pain, as animals self-control the
administration of analgesics depending on the subjective pain sensa-
tion. Therefore, this novel preclinical model has a high predictive
value to estimate the clinical benefit/risk ratio of new analgesic com-
pounds. Another point to be taken into consideration to circumvent
possible long-term risks associated with therapeutic use of cannabi-
noids would be the administration route. Current cannabinoid formu-
lations are administered as oromucosal spray, by classical oral pills
or by inhalation, whereas the transdermal route is currently being
explored in animal studies (Fitzcharles et al., 2012). Most of the
cannabinoids under investigation could present limitations for sys-
temic administration due to their undesired systemic effects, espe-
cially in the context of chronic treatment, such as in osteoarthritis.
Therefore, an additional approach would be to modulate the endoc-
annabinoid system primarily in the affected joints by intra-articular
administration of the drugs. A great challenge for the research in
this field is to increase the retention time of the therapeutic agent in
the joint as most agents are rapidly cleared after intra-articular injec-
tion (Morgen et al., 2013).
Concluding remarks
Cannabinoids represent emerging and innovative pharmacological
tools of potential interest for the treatment of osteoarthritis. Thus,
the pharmacological studies show the anti-nociceptive effects of
cannabinoids in rodent models of osteoarthritis, and compelling evi-
dence suggests an active participation of the endocannabinoid sys-
tem in the pathophysiology of this disease. Despite these promising
preclinical data, limited evidence is available so far to support the
clinical use of cannabinoids for osteoarthritis pain management. The
failure of an initial clinical trial with a FAAH inhibitor reveals
the complexity of this disease and encourages the design of novel
clinical trials in other experimental conditions and/or with other
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
European Journal of Neuroscience, 39, 485–500
Cannabinoid system in osteoarthritis 495
cannabinoid compounds. The potential effect of cannabinoids in
slowing the disease progression still remains to be explored. Further
studies are therefore required to evaluate the potential effectiveness
of cannabinoids as an innovative strategy for osteoarthritis treatment.
Clinical trials should be promoted to determine the possible transla-
tion to humans of the very promising results already obtained in the
preclinical studies.
Conflict of interest
The authors declare no competing interests.
Acknowledgements
This work was supported by the Spanish ‘Ministerio de Ciencia e Innovac-
on’ (SAF2011-29864), ‘Instituto de Salud Carlos III’ (RETICS-Red de Tra-
i
stornos Adictivos-Redes Tematicas de Investigaci on Cooperativa en Salud:
#RD06/0001/0001, #RD06/0001/1004), Plan Nacional sobre Drogas (PNSD
#2009/026), the Catalan Government (SGR2009-00131) and the ICREA
Foundation (ICREA Academia-2008). Important contributions from several
authors could not be included due to space limitations.
Abbreviations
2-AG, 2-arachidonoylglycerol; ACEA, arachidonyl-2-chloroethylamide;
ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs;
AEA, N-arachidonoyl ethanolamine; CB1R, cannabinoid receptor 1; CB2R,
cannabinoid receptor 2; COX-2, cyclooxygenase-2; FAAH, fatty-acid amide
hydrolase; GABA, c-aminobutyric acid; IL, interleukin; iNOS, inducible
nitric oxide synthase; MAGL, monoacylglycerol lipase; MIA, sodium mono-
iodoacetate; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory
9
drugs; PGE2, prostaglandin E2; THC, D -tetrahydrocannabinol; TRPV-1,
transient receptor potential vanilloid-1.
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