Endocanabinoides en Manejo Del Dolor
Transcript of Endocanabinoides en Manejo Del Dolor
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R E V I E W
A R T I C L E
The role of endocannabinoids in pain
modulation
Panagiotis Zogopoulos, Ioanna Vasileiou, Efstratios Patsouris, Stamatios
E. Theocharis*
First Department of Pathology, Medical School, University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens,Greece
Keywords
2-arachidonoylglycerol,
analgesia,
anandamide,
N-arachidonoylethanol-
amine,
antinociception,
CB receptors,
endocannabinoids
Received 28 November 2011;
revised 3 September 2012;
accepted 21 September 2012
*Correspondence and reprints:
A B S T R A C T
The endocannabinoid system (ES) is comprised of cannabinoid (CB) receptors, their
endogenous ligands (endocannabinoids), and proteins responsible for their metabo-
lism. Endocannabinoids serve as retrograde signaling messengers in GABAergic and
glutamatergic synapses, as well as modulators of postsynaptic transmission, that
interact with other neurotransmitters. Physiological stimuli and pathological condi-
tions lead to differential increases in brain endocannabinoids that regulate distinctbiological functions. Furthermore, endocannabinoids modulate neuronal, glial, and
endothelial cell function and exert neuromodulatory, anti-excitotoxic, anti-inflam-
matory, and vasodilatory effects. Analgesia is one of the principal therapeutic tar-
gets of cannabinoids. Cannabinoid analgesia is based on the suppression of spinal
and thalamic nociceptive neurons, but peripheral sites of action have also been
identified. The chronic pain that occasionally follows peripheral nerve injury differs
fundamentally from inflammatory pain and is an area of considerable unmet thera-
peutic need. Over the last years, considerable progress has been made in under-
standing the role of the ES in the modulation of pain. Endocannabinoids have been
shown to behave as analgesics in models of both acute nociception and clinical pain
such as inflammation and painful neuropathy. The framework for such analgesic
effects exists in the CB receptors, which are found in areas of the nervous systemimportant for pain processing and in immune cells that regulate the neuro-immune
interactions that mediate the inflammatory hyperalgesia. The purpose of this review
is to present the available research and clinical data, up to date, regarding the ES
and its role in pain modulation, as well as its possible therapeutic perspectives.
I N T R O D U C T I O N
Cannabinoids, first discovered in the 1940s, are a class
of chemical compounds that include the phytocannabi-
noids (oxygen-containing C21 aromatic hydrocarboncompounds found in the cannabis plant) and chemical
compounds that mimic the actions of phytocannabi-
noids or have a similar chemical structure [1,2]. Syn-
thetic cannabinoids encompass a variety of distinct
chemical classes: the classical cannabinoids structurally
related to D9-tetrahydrocannabinol (D9-THC), the non-
classical cannabinoids including the aminoalkylindoles,
1,5-diarylpyrazoles, quinolines, and arylsulfonamides,
as well as eicosanoids related to the endocannabinoids.
D9-THC (the primary psychoactive component of the
cannabis plant), cannabidiol (CBD), and cannabinol
(CBN) are the most prevalent natural cannabinoids
and have been mostly studied. Cannabinoids can beadministered by smoking, vaporizing, oral ingestion,
transdermal patch, intravenous injection, sublingual
absorption, or rectal suppository. Most cannabinoids
are metabolized in the liver, especially by cytochrome
P450 (CYP) mixed-function oxidases, mainly CYP 2C9
[1,2].
Over the last decades, several studies have reported the
existence of an endogenous lipid signaling system with
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doi: 10.1111/fcp.12008
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cannabimimetic actions, referred to as endocannabinoid
system (ES). Recent pharmacological advances have
enabled the study of the physiological roles played by the
ES, including its role in analgesia. The purpose of this
review is to present current knowledge about the role of
the ES in pain modulation and consequently the future
prospects of developing potential analgesic agents.
T H E E N D O C A N N A B I N O I D S Y S T E M
The ES is involved in a variety of physiological pro-
cesses including nociception (pain sensation), appetite,
lipid metabolism, gastrointestinal motility, cardiovascu-
lar modulation, motor activity, mood, and memory
[35]. It is comprised of cannabinoid receptor type-1
(CB1) and type-2 (CB2), which are seven-transmem-
brane, G-protein coupled receptors negatively coupled
to adenylyl cyclase and positively coupled to mitogen-activated protein kinase (MAPK)[6,7]. It also includes
their endogenous lipid-based ligands, the endocannabi-
noids, of which anandamide (N-arachidonoylethanol-
amine, AEA) and 2-arachidonoylglycerol (2-AG) are
mostly studied [8,9], and the proteins that are respon-
sible for their biosynthesis, transport, and degradation
[10].
Cannabinoid receptors
CB1 receptors are most abundantly expressed in the
mammalian brain and also in peripheral tissues
[11,12]. They are highly expressed in regions of thebrain, such as the cortex, limbic system, hippocampus,
cerebellum, brainstem, and several nuclei in the basal
ganglia that are associated with emotion, cognition,
memory, motor and executive function [13]. More
specifically, they are expressed in brain areas involved
in nociceptive transmission and processing, including
the periaqueductal gray (PAG), anterior cingulate cor-
tex (ACC), and thalamus in addition to the dorsal horn
of the spinal cord and dorsal root ganglion (DRG)[14
16]. CB1 receptors are found primarily at the terminals
and also at the axons, at cell bodies, and at dendrites
of central and peripheral neurons, where they typicallymediate the inhibition of amino acid and monoamine
neurotransmitter release, as occurs with the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA)
[17,18].
CB2 receptors in the brain are expressed primarily in
the perivascular microglial cells [19,20] and astrocytes
[21,22], where they modulate the immune responses
[2325]. They are also expressed in cerebromicrovas-
cular endothelial cells [26] and in central (brainstem)
and peripheral neurons [2729]. Furthermore, CB2
receptors are found on the cells of the immune system
throughout the whole body [i.e., B lymphocytes, mac-
rophages, natural killer (NK) cells] [30,31], and they
are also expressed in the myocardium, the human cor-
onary endothelial cells, the smooth muscle cells, and
the liver [11,12,32].
Ligands
Endocannabinoids are endogenous metabolites of
eicosanoid fatty acids. They are lipid signaling
mediators of the same CB receptors that mediate the
effects of D9-THC [33,34]. They are derivatives of ara-
chidonic acid conjugated with either ethanolamine or
glycerol. Apart from anandamide (AEA) and 2-arachi-
donoylglycerol (2-AG), which are the best described
endocannabinoids, N-arachidonoyldopamine (NADA),
2-arachidonoylglyceryl ether (2-AGE, noladin ether), and
O-arachidonoylethanolamine (OAE, virodhamine) are also
included [8,3537] (Figure 1).
AEA, the first endocannabinoid to be identified [8],
appears to be a partial agonist for CB1 receptor [38]
with modest affinity [Ki = 61 nM (rat) and 240 nM
(human)] and a relatively weak CB2 receptor ligand
(Ki = 4401930 nM for rodent and human CB2 recep-
tors) with low overall efficacy. More recent data sug-
gest that it might also interact directly with other
molecular targets, including non-CB1, non-CB2 G-pro-
tein coupled receptors, gap junctions, and various ionchannels [3942].
2-AG, the second identified CB receptor ligand
[43,44], is the most abundant endocannabinoid in the
central nervous system (CNS) and a full agonist for
both CB1 and CB2 receptors [34,38,45] with lower
affinity (Ki = 472 and 1400 nM, respectively) and
greater efficacy relatively to AEA [46,47].
NADA was discovered in 2000 and preferentially
binds to the CB1 receptor [48]. The distribution pattern
of endogenous NADA in various brain areas differs
from that of AEA, with the highest levels found in the
striatum and hippocampus [35], while it, also, exists inthe DRG at low levels [49]. 2-AGE, isolated in 2001
from porcine brain, binds primarily to the CB1 receptor
(Ki = 21.2 nM) and only weakly to the CB2 receptor
[50].
OAE, discovered in 2002, is a compound similar to
AEA in being formed from arachidonic acid and
ethanolamine, but OAE contains an ester linkage rather
than AEAs amide linkage. Although it is a full agonist
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for CB2 receptor and a partial agonist for CB1 receptor,
it behaves as a CB1 antagonist in vivo. In rats, OAE was
found to be present at comparable or slightly lower con-
centrations than AEA in the brain, but 2- to 9-fold
higher concentrations peripherally [36].
Biosynthesis
Unlike traditional neurotransmitters such as acetylcho-
line and dopamine, endogenous cannabinoids are notstored in vesicles after synthesis, but are synthesized on
demand from phospholipid precursors residing in the
cell membrane in response to a rise in intracellular cal-
cium levels [4,37,51]. However, some evidence sug-
gests that a pool of synthesized endocannabinoids
(namely, 2-AG) may exist without the requirement of
on-demand synthesis [52].
Endocannabinoid levels are elevated in brain paren-
chyma as part of internal repair responses to traumatic
brain and spinal cord injuries [53,54]. Enzymatic syn-
thesis of both AEA and 2-AG draws upon pools of mem-
brane phospholipids such as phosphatidylethanolamine(PE), phosphatidylcholine (PC), and phosphatidylinositol
4,5-bisphosphate [55,56]. It is worth mentioning that
hormones of the gonadal axis, such as estradiol, regu-
late the expression of the enzymes involved in the syn-
thesis and metabolism of endocannabinoids in different
peripheral tissues [57].
AEA and its precursor, N-arachidonoylphosphatidyl-
ethanolamine (NAPE), are normally expressed at low
concentrations in the rat brain, but increase in a cal-
cium-dependent manner postmortem [58] and after
severe neuronal injury [38,59]. A two-step biosynthesis
pathway of AEA has been suggested, involving the
sequential action of a calcium-dependent transacylase
(Ca-TA, N-acyltransferase) and a NAPE-selective phos-
pholipase D (NAPE-PLD). N-acyltransferase transfers a
fatty acyl chain from a membrane phospholipid mole-
cule onto the primary amine of membrane, phosphati-dyl-ethanolamine, to generate NAPE, and NAPE-PLD
hydrolyzes NAPE to N-acylethanolamines (NAEs) such
as AEA [6062] (Figure 2). AEA can also be formed by
the stimulation of dopamine D2 receptors in a G-pro-
tein-coupled process [63].
2-AG is synthesized from diacylglycerol (DAG) by
diacylglycerol lipase (DAGL). DAGL is found at
increased levels after neuronal injury [28,64] and
catalyzes the hydrolysis of DAG, releasing a free fatty
acid and monoacylglycerol, which is then converted to
2-AG [13,65] (Figure 3). AEA levels increase is fol-
lowed by 2-AG upregulation [54]. The accumulation of2-AG at the site of injury has been described to present
a peak 4 h after injury and sustained up to at least
24 h postinjury [66].
Transport and metabolism
Endocannabinoids serve as retrograde signaling
messengers in GABAergic and glutamatergic synapses,
as well as modulators of postsynaptic transmission,
Figure 1 Biosynthesis, transport anddegradation of endocannabinoids.
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interacting with other neurotransmitters, including
norepinephrine and dopamine [67]. 2-AG and AEA are
removed from extracellular space and transported into
cells through a diffusion-facilitated transporter system
or uptaken via membrane-associated carrier and simple
diffusion [68]. Thus, endocannabinoid signaling func-
tions are efficiently terminated by cellular uptake and
rapid, enzyme-catalyzed hydrolytic inactivation. Fatty
acid amide hydrolase (FAAH) and monoacylglycerol
lipase (MAGL) are the primary catabolic enzymes of
AEA and 2-AG, respectively [6972]. A partly cytosolic
variant of FAAH, termed FAAH-like anandamide trans-
porter, has been shown to bind AEA with low micro-
molar affinity and facilitate its translocation into cells
[73].
FAAH is highly expressed by neurons in the mamma-
lian brain as an integral membrane protein and is upreg-
ulated after neuronal injury [28,64]. It is localized in
endoplasmic reticulum of hippocampus, neocortex, and
cerebellum [55,74] and catalyzes the hydrolysis of sev-
eral endogenous, biologically active lipids, including
AEA, oleoyl ethanolamide (OEA), and palmitoyl ethan-
olamide (PEA)[75]. AEA has a short half-life, as it is rap-
idly hydrolyzed by FAAH, and its resting concentrations
in the CNS are very low. FAAH degrades AEA into
arachidonic acid and ethanolamine, after its release from
neurons [72,76]. Enhanced cannabinoid signaling can
be achieved by preventing AEA hydrolysis/inactivation
by FAAH. A number of FAAH inhibitors exist that can
increase the level of AEA in the brain of experimental
animals [55].
On the other hand, FAAH has been also demon-
strated to catalyze AEA synthesis from arachidonic acid
and ethanolamine, with a reported Km for ethanol-
amine of at least 36 mM [77]. Several studies have
shown that recombinant FAAH protein acts as an AEA
synthetase if the concentration of ethanolamine is very
high (100 mM) and is capable of catalyzing the reverse
of the hydrolase reaction [78,79].
2-AG is hydrolyzed into arachidonic acid and
glycerol by either FAAH or preferably by MAGL
[51,75,80]. 2-AG has been shown to be a substrate for
FAAH both in vitro [69,81] and in vivo [82].
Recent evidence reveals that endogenous cannabi-
noids are also substrates for cyclo-oxygenase (COX) and
can be selectively oxygenated by a COX-2 pathway to
form new classes of prostaglandins (prostaglandin glyc-
erol esters and prostaglandin ethanolamides) [8385].
Therefore, this is another pathway in degrading
endocannabinoids in addition to their well-known
Figure 2 The AEA biosynthesis
pathway.
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hydrolysis pathways. Metabolites of AEA and 2-AG,
derived from COX-2, have biological activity, including
the activation of protein kinase C (PKC) and also have
effects on the contractility of smooth muscle prepara-
tions [86,87]. Prostanoids derived from both AEA and
2-AG are significantly more stable metabolically than
free-acid prostaglandins, suggesting that COX-2 action
on endocannabinoids may provide oxygenated lipids
with sufficiently long half-lives to act as systemic
mediators or prodrugs [88,89].
Signaling pathways and molecular targets
The neuromodulatory and anti-inflammatory effects of
cannabinoids are mediated by induction of apoptosis,
inhibition of cell proliferation, suppression of cytokine
production, and induction of T-regulatory cells. One
major mechanism of immunosuppression by cannabi-
noids is the induction of cell death or apoptosis in
immune cell populations, thus playing a protective role
in autoimmune conditions [37,90].
In vitro and in vivo studies have shown that cannabi-
noids can act on glia and neurons to inhibit the release
of pro-inflammatory cytokines [tumor necrosis factor-a
(TNF-a), interleukin (IL)-6, and IL-1b] and enhance
the release of anti-inflammatory factors such as the
cytokines IL-4 and IL-10 [21,9193]. AEA, via the
activation of CB1 receptors, enhances the synthesis of
IL-6, which has both pro- and anti-inflammatory prop-
erties, and reduces the synthesis of the proinflammato-
ry cytokine TNF-a in Theilers virusinfected astrocytes
[94].
CB receptors initiate different signaling pathways
including adenylyl cyclase and protein kinase A (PKA)
inhibition and regulation of ionic channels. CB1 agon-
ists reduce calcium influx by blocking the activity of
voltage-dependent N-, P/Q-, and L-type calcium (Ca2+)
channels [95,96]. This leads to reduced activity of neu-
ronal nitric oxide synthase (nNOS) but also to the
reduction of other potentially damaging reactive oxy-
gen species [9799]. CB1 activation can also initiate
the opening of inwardly rectifying K+ channels and the
inhibition of adenylyl cyclase activity, resulting in a
decrease in cytosolic cAMP [34,100,101]. In addition,
regulation of neuronal gene expression by CB1 recep-
tors depends on the recruitment of complex networks
of intracellular protein kinases, such as the phosphati-
Figure 3 The 2-AG biosynthesis
pathway.
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dylinositol 3-kinase/Akt, the extracellular signal-regu-
lated kinase (ERK), and the focal adhesion kinase,
which become activated when hippocampal brain tis-
sue is treated with cannabinoid agonists according to
the findings of experimental studies [102,103]. CB1
receptors also modulate the generation of sphingolipid-
derived signaling mediators and cell death pathways
(e.g., caspase activation and the endoplasmic reticulum
stress response) [104].
AEA can inhibit a number of different ion channels
[105], and it appears that there is a direct extracellular
binding site for AEA on these channels. AEA has been
demonstrated to activate the transient receptor poten-
tial vanilloid 1 (TRPV1) both in vitro and in vivo
[45,106,107] and to upregulate genes involved in pro-
inflammatory microglial-related responses [108,109].
TRPV1 receptors are nonselective ion channels whose
location in sensory neurons allows them to gate
responses to painful stimuli such as high temperature
and low pH. Activation of TRPV1 leads to an increased
influx of Ca2+ [110], glutamate release [111], and sub-
stantial contribution to neuronal excitotoxicity that
leads to apoptosis [108,112].
CB2 receptors mediate anti-inflammatory actions of
cannabinoids on astrocytes and microglia. In particu-
lar, they decrease the activity of antigen-presenting
cells and downregulate cytokine (IFN-c, TNF-a, and
IL-6) production during inflammatory responses in in
vivo and in vitro studies [113,114]. The anti-inflamma-
tory effects of cannabinoids on glial cells involve theinhibition of nuclear factor jB (NF-jB)-induced tran-
scription of proinflammatory chemokines and cytokines
[115,116]. Moreover, CB2 receptors might control
immune cell proliferation by coupling to ERK activa-
tion (independent of cAMP) via regulation of mkp-1
gene expression by histone H3 phosphorylation [117].
AEA induces rapid phosphorylation of histone H3 on
the mkp-1 gene and also induces mkp-1 expression in
microglial cells of inflammatory brain lesions, which
suppresses nitric oxide (NO) release and inflammatory
damage in living brain tissue [118].
Endocannabinoids mainly induce an inhibitory effecton both GABAergic and glutamatergic neurotransmis-
sion and neurotransmitter release, although the results
are somewhat variable [119121]. In some cases,
cannabinoids diminish the effects of GABA, while in
others they can augment the effects of GABA. The
effect of activating a receptor depends on where it is
expressed on the neuron: if CB receptors are
presynaptic and inhibit the release of GABA, cannabi-
noids would diminish GABA effects; the net effect
would be stimulation. However, if CB receptors are
postsynaptic and on the same cell as GABA receptors,
they would probably mimic the effects of GABA; in
that case, the net effect would be inhibition [122]. En-
docannabinoids induce these effects via the phenome-
non of depolarization-induced suppression of inhibition
(DSI). DSI refers to endocannabinoid-induced suppres-
sion of GABAergic synaptic transmission. In DSI,
strong depolarization of a postsynaptic neuron induces
a release of signal that acts on the presynaptic CB1
receptor and transiently inhibits the release of GABA.
Such retrograde signaling by endocannabinoid-medi-
ated DSI occurs in the hippocampus but has also been
shown outside the hippocampus at interneuron-princi-
pal cell synapses [123]. Thereafter, a similar phenome-
non has been demonstrated for glutamatergic synaptic
transmission and has been designated depolarization-
induced suppression of excitation (DSE) [124,125].
Cannabinoids attenuate glutamate-induced injury by
inhibiting glutamate release via presynaptic CB1 recep-
tors coupled to G-proteins and N-type voltage-gated
calcium channels [97,126]. 2-AG, but not AEA, is pos-
sibly a signaling molecule in mediating CB1-dependent
DSI or DSE [34,127]. Moreover, enzymes that synthe-
size 2-AG are present in postsynaptic dendritic spines,
providing direct evidence that 2-AG is synthesized in
postsynaptic sites and acts on presynaptic CB1 recep-
tors [128,129]. Thus, endocannabinoids (especially
2-AG) are proposed to serve as retrograde messengersin modulating both GABAergic and glutamatergic
synaptic transmission [120,121,130,131].
E N D O C A N N A B I N O I D S A N D P A I N
M O D U L A T I O N
Analgesia is one of the principal therapeutic targets of
cannabinoids. The chronic pain that occasionally fol-
lows peripheral nerve injury differs fundamentally from
inflammatory pain and is an area of considerable,
unmet therapeutic need [64,132135]. Several investi-
gations have gathered important experimental andclinical data about the analgesic properties of cannabi-
noids and their endogenous counterparts.
Experimental data
Sites of analgesic action
Cannabinoid administration has been found to suppress
behavioral and neurophysiological responses to all
types of nociceptive stimuli tested. It suppresses both
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wide dynamic range neurons (mediating response to
touch and pain) and nociceptive-specific neurons that
mediate response to pain only, but does not affect low-
threshold mechanoreceptive neurons that mediate
response to touch only [136]. Cannabinoids have been
found in many studies to exert their analgesic effects
by an action in the brain via descending modulation,
by a direct spinal action, and/or by an action on the
peripheral nerve [136140]. As highly lipophilic
compounds, cannabinoids can readily penetrate the
bloodbrain barrier and access the brain [23,24]. This
is followed by the induction of antinociceptive effects
through actions in the PAG and the rostral ventrolat-
eral medulla (RVM), whose circuits inhibit spinal noci-
ceptive neurotransmission [136140]. The ACC is part
of the medial pain pathway and has been shown to be
involved in the affective component of pain processing
[141]. A recent research has shown that CB receptor
mediated G-protein activity in the rostral anterior cin-
gulate cortex (rACC) of mice is decreased after 10 days
of chronic constriction injury (CCI), perhaps in an
attempt to minimize the feeling of pain [142]. Experi-
mental studies have demonstrated that microinjection
of cannabinoids into sites such as the dorsolateral
PAG, dorsal raphe nucleus, RVM, amygdala, lateral
posterior and submedius regions of the thalamus, supe-
rior colliculus, and noradrenergic A5 region produces
antinociception [137140,143145]. Furthermore, sys-
temically inactive doses of cannabinoids have been
shown to attenuate carrageenan-evoked allodynia andhyperalgesia, when administered peripherally, and sup-
press carrageenan-evoked Fos protein (a marker of
neuronal activity) expression in the lumbar dorsal horn
of the spinal cord in rats [146]. At the level of the
spinal cord, CB2 receptors activation has analgesic
effects in neuropathic rats [147,162]. Thus, both
peripheral and spinal cord injections of cannabinoids
have been shown to be antinociceptive.
Pain models
Animal studies have firmly established cannabinoid-
induced analgesia in a wide array of pain models
[143,144] (Table I). In models of acute or physiologi-
cal pain, cannabinoids are highly effective against
thermal [148], mechanical [149], and chemical pain
[149,150], and typically, cannabinoids were compara-
ble with opiates (both in potency and efficacy) in pro-
ducing antinociception [148]. On the other hand, in
models of tonic or chronic pain, both inflammatory
[151] and neuropathic [152] cannabinoids have
shown even greater potency and efficacy. D9-THC,
which has approximately equal affinity for the CB1
and CB2 receptors, appears to ease moderate pain andto be neuroprotective [2]. It is likely that high doses of
D9-THC would be effective in pain management, but,
unfortunately, these doses also produce undesirable
CNS effects.
Neuropathic pain is defined as pain arising as a
direct consequence of a lesion or disease affecting the
somatosensory system. It can be caused by several dis-
orders, like nerve injury, diabetes, viral infection, and
chemotherapic agents [134,152]. Both CB and TRPV1
receptors are upregulated in the spinal cord and DRG
of neuropathic rats [64,152]. Molecules that are inhibi-
tors of endocannabinoid cellular re-uptake and are alsoagonists for TRPV1 receptors, such as AM404 and
arvanil, are very effective against both thermic hyperal-
gesia and mechanical allodynia in the CCI model of
neuropathic pain [153,154]. The antinociceptive
responses to D9-THC and other cannabinoids are
Table I Antinociceptive effects of cannabinoids on various pain models
Agent Animal subject Pain test Pain model Results References
AEA Rats Thermal allodynia Inflammatory Reduced hyperalgesia Karbarz et al. (2009) [75]
2-AG Mice CHI Acute/Inflammatory Inhibition of pro-inflammatory
cytokines
Panikashvili et al.
(2006) [196]
AEA/2-AG Rats CCI
mechanical/thermal
allodynia
Neuropathic Anti-nociception Petrosino et al.,
(2007) [157]
URB597 (FAAH
inhibitor)
Mice CCI mechanical/cold
allodynia
Neuropathic Attenuation of allodynia Kinsey et al. (2009) [159]
OL135 (FAAH
inhibitor) + AEA/2-AG
Mice MTI mec ha nic al al lodynia Acute Att enuat ion of a ll odynia Pal mer et a l. (2008) [195]
D9-THC Rats Thermal allodynia Acute Antinociception Martin et al. (1999)
[139,140]
AEA, anandamide, N-arachidonoylethanolamine; CCI, chronic constriction injury, MTI, mild thermal injury; CHI, closed head injury.
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absent or markedly attenuated in CB1 knockout
mice [155]. Moreover, peripheral deletion of CB1 on
nociceptors (with CB1 preserved in the CNS) can
block the analgesic effects of locally and systemically
administered cannabinoids [156]. In the spinal cord,
the elevation of AEA levels appears to be an early
observed already after 3 days and strong event
accompanying CCI of the sciatic nerve, followed also
by a significant elevation in 2-AG levels 7 days after
the surgery [157]. This differential effect on the two
major endocannabinoids might have a functional sig-
nificance as 2-AG is able to activate both CB1 and CB2
receptors, whereas AEA can only activate the former
receptor type, but can instead gate TRPV1 channels.
Therefore, it can be assumed that AEA levels are ele-
vated at both 3 and 7 days from CCI as an adaptive
response aimed at targeting first the CB1 receptor,
which is already present in the spinal cord even prior
to the development of pain following nerve constric-
tion. The TRPV1 receptor is activated later, when the
expression of this protein is strongly elevated and par-
ticipates in thermal hyperalgesia [158]. Likewise, 2-AG
levels might be elevated only 7 days after CCI to acti-
vate CB2 receptors, which are also upregulated only
following the full development of neuropathic pain (i.e.,
starting 4 days from surgery). CB2 receptor stimulation
has been found to decrease allodynia at the level of
peripheral nociceptors, spinal nerves, and afferents, or
supraspinally [64,157,159]. The levels of the two
major endocannabinoids, AEA and 2-AG, increase fol-lowing CCI of the sciatic nerve in both the spinal cord
and in some supraspinal areas involved in the descend-
ing control of nociception and of some of its emotional
components. Therefore, the ES might become chroni-
cally activated as an adaptive response to neuropathic
pain aiming at counteracting pain transmission [157].
It can be, thus, explained why inhibitors of endocanna-
binoid inactivation can exert analgesic effects in this
experimental model of pain.
There have been several reports on the analgesic
efficacy of pharmacological inhibition of FAAH using
different chemical classes of inhibitors such as a-keto-heterocycle compounds, carbamates, and analogues of
N-arachidonoyl serotonin [75]. FAAH inhibition
enhances the analgesic properties of AEA, as they would
accumulate to higher levels in the absence of hydrolysis.
This was confirmed in the FAAH knockout mice pro-
duced by Cravatt et al. [76] that had enhanced levels of
AEA and exhibited a hypoalgesic phenotype in several
pain models. The anti-allodynic effects of the FAAH
inhibitors, in several clinical studies, were fully reversed
by pretreatment with either CB1 (i.e., SR141716A) or
CB2 receptor antagonists, but were unaffected by the
TRPV1 receptor antagonist, capsazepine [159].
CB receptor agonists are active in animal models of
acute pain when they are either administered peripher-
ally or injected directly into the brain or spinal cord.
Locally administered AEA has been shown to attenuate
carrageenan-induced thermal hyperalgesia and cutane-
ous edema [160]. Endogenous fatty acid derivatives
such as oleamide, palmitoylethanolamide, 2-lineoylglyc-
erol, 2-palmitoylglycerol, and a family of arachidonoyl
amino acids may also interact with endocannabinoids in
the modulation of pain sensitivity [136]. NADA elicits a
host of cannabimimetic effects, including analgesia after
systemic administration. It is noteworthy that NADA,
through the activation of TRPV1, causes hyperalgesia
when administered peripherally [35,161]. Given that
NADA is capable of eliciting analgesia upon systemic
administration and hyperalgesia upon intradermal injec-
tion, it is possible that endogenous NADA may acti-
vate either CB1 or TRPV1 depending on location
and circumstance. Apart from NADA, 2-AGE has been
reported, in experimental models, to induce sedation,
hypothermia, intestinal immobility, and mild antinoci-
ception in mice [2]. Animal experimental models using
tail flick, hot plate, or radiant heat paw withdrawal tests
have shown that cannabinoids can interact synergisti-
cally with opioid receptor agonists in the production of
antinociception. This synergism seems to be receptormediated as it can be blocked by both cannabinoid and
opioid receptor antagonists [162,163]. The suppression
of motor responses to noxious stimuli induced by CB1
receptor agonists in animal pain models does not seem
to stem from the known ability of these agents to impair
motor function or to induce hypothermia. Thus, the
analgesic effects of cannabinoids have been found to be
due to the suppression of spinal and thalamic nocicep-
tive neurons and independent of any actions on
either the motor system or sensory neurons that trans-
mit messages related to non-nociceptive stimulation
[136].
Synthetic cannabinoids
The antinociceptive potency of D9-THC is no less than
that of morphine, an agent already known to induce
receptor-mediated analgesia [143, 162164]. A number
of cannabinoids show even greater potency than D9-
THC, for example, in the mouse tail flick test, after intra-
venous administration [137,144]. A wide variety of
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synthetic cannabinoids have been produced that interact
with CB receptors. Experimental studies have shown
that activation of the CB1 receptor by synthetic agon-
ists, and pharmacological elevation of endocannabinoid
levels, suppress hyperalgesia and allodynia in animal
models of neuropathic pain [165,166]. Systemic admin-
istration of the CB receptor agonist Win55,212-2 dose-
dependently reversed the thermal hyperalgesia and the
mechanical and cold allodynia by a CB1, but not CB2
receptor-mediated effect [167]. Win55,212-2 has also
been reported to be effective after intrathecal and
peripheral administration in doses not systemically
active, suggesting that a potential peripheral site of
action may be exploited to divorce the psychotropic
effects of cannabinoids from their analgesic effects
[167]. Bay 38-7271, another synthetic cannabinoid
agonist, exerts analgesic and neuroprotective effects after
traumatic brain injury in rats [168]. The selective
CB1 receptor antagonist, SR141716A, can prevent the
antinociceptive effects of CB receptor agonists at an
appropriately high potency. It is important to bear in
mind that, although SR141716A is CB1-selective, it is
not CB1 specific and will, at sufficiently high doses,
block CB2 as well as CB1 receptors [169].
Clinical data
It is generally accepted that opioid analgesics are less
effective when used for the treatment of neuropathic
pain in comparison with inflammatory pain. One
explanation for this is that following peripheral nerveinjury, there is a depletion of opioid receptor expression
in the spinal dorsal horn [170,171]. However, the
destruction of primary afferent input to the dorsal
horn, by dorsal rhizotomy [16] or neonatal capsaicin
therapy [171], is not associated with such a depletion
of CB1 receptor-like immunoreactivity or binding, thus
giving cannabinoids a potential therapeutic advantage
over opioids in neuropathic pain. Moreover, cannabi-
noids may also be particularly efficacious in patient
populations where the emetic effects of opioids are
poorly tolerated, for example, in patients with cancer
and patients with HIV infection [37].
Side effects
The development of cannabinoid agonists as analgesics
has been hampered due to psychotropic and debilitating
side effects. The most common adverse events associ-
ated with the use of cannabis are headache, dry eyes,
burning sensation in areas of neuropathic pain, dizzi-
ness, numbness, cough, and effects on memory and on
motor control that occur as a result of indiscriminate
activation of CB receptors at sites other than those
involved in the transmission of nociceptive stimuli
[172,173]. Efforts are currently under way to develop
inhalational forms ofD9-THC that may possibly be more
effective than an oral formulation in managing cancer
pain, either alone or in combination with other analge-
sics [130,174]. It is noteworthy that in vivo cannabi-
noid administration has been reported to be neurotoxic
[175]. Moreover, there is a significant abuse potential,
which has hindered their development as therapeutic
agents [176]. Nevertheless, the synthetic cannabinoid
abn-CBD represents a promising candidate for treatment
of neuronal injury in vivo because it does not bind to
CB1 and CB2 receptors and may thus produce less
undesired side effects [177]. Therefore, a possible way
to have its benefits, while you avoid its side effects, is to
manipulate the endogenous cannabinoid system.
Endocannabinoid analgesia
As endocannabinoids exert their actions through the
same targets (CB1 and CB2 receptors) with D9-THC
and other exogenous cannabinoids, there are indica-
tions that they share common analgesic properties.
Multiple lines of evidence indicate that endocannabi-
noids serve naturally to suppress pain. Physiological
stimuli and pathological conditions lead to differential
increases in brain endocannabinoids that regulate dis-
tinct biological functions. Physiological stimuli lead to
rapid and transient (seconds to minutes) increases inendocannabinoids that activate neuronal CB1 recep-
tors, modulate ion channels, and inhibit neurotrans-
mission [125], whereas pathological conditions lead
to much slower and sustained (hours to days)
increases in the endocannabinoid tone that changes
gene expression, implementing molecular mechanisms
that prevent the production and diffusion of harmful
mediators [178180].
While a proportion of the peripheral analgesic effects
of endocannabinoids can be attributed to a neuronal
mechanism acting through CB1 receptors expressed by
primary afferent neurones, the anti-inflammatoryactions of endocannabinoids are mediated through CB2
receptors that have also been found to participate in
pain modulation [181]. Activation of the CB1 receptor
inhibits the transmitter release from nociceptive pri-
mary afferent fibers both at the periphery and the CNS.
The GABA release within the PAG and RVM and the
glutamate release within the spinal cord are inhibited
[160]. Presynaptic inhibition is a particularly powerful
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mechanism of neural modulation, as it can have the
final determinant influence on the output signal of a
neuron and its subsequent communication to other
neurons.
Clinical trials
In human clinical trials, administration of CB receptor
agonists has been shown to be effective in treating neu-
ropathic pain conditions and, in some instances, rival
the analgesic efficacy of morphine [182,183]. A clinical
trial in healthy volunteers revealed that low doses of
smoked cannabis (D9-THC) can reduce the pain
induced by intradermal capsaicin, while at higher doses
the pain is increased [184]. Another study in patients
with advanced cancer showed that the combined
administration of D9-THC and CBD resulted in a statis-
tically significant reduction in pain [185]. Smoked can-
nabis has also been shown to effectively relieve chronicneuropathic pain from HIV-associated sensory neuropa-
thy, and its use is generally well tolerated [186]. Cann-
abinoids that have been approved in USA or Europe
include dronabinol (MarinolTM, approved in USA, UK,
and Canada), nabilone (CesametTM, approved in USA,
UK, Canada, and Mexico), and GW-100 (SativexTM, a
combination ofD9-THC and CBD, approved in UK, Can-
ada, Spain, Czech Republic, Germany, and Denmark).
However, all of these drugs contain D9-THC or an ana-
logue and are nonselective with respect to CB1 and
CB2 receptors. In several clinical studies, patients with
multiple sclerosis have reported the benefits of D
9
-THCand the CB receptor agonist nabilone, in treating spas-
ticity, pain, tremor, and ataxia [187,188].
C O N C L U S I O N
Over the last years, considerable progress has been
made in understanding the role of endocannabinoids in
pain modulation. The ES represents a local messenger
between the nervous and immune system and is
obviously involved in the control of immune activation
and neuroprotection. Manipulation of endocannabi-
noids and/or use of exogenous cannabinoids in vivocan constitute a potent treatment modality against
inflammatory disorders. Cannabinoids have been tested
in several experimental models of autoimmune disor-
ders such as multiple sclerosis, rheumatoid arthritis,
colitis, and hepatitis and have been shown to protect
the host from the pathogenesis through induction of
multiple anti-inflammatory pathways and consequently
they also contribute to antinociception.
Endocannabinoid signaling may be enhanced indi-
rectly to therapeutic levels through FAAH inhibition,
thus prolonging the duration of action of endogenously
released AEA. Therefore, FAAH serves as an attrac-
tive pharmacotherapeutic target and selective FAAH
inhibitors as promising analgesic candidates for various
neurological and neurodegenerative/neuroinflammato-
ry disorders, including seizures of diverse etiology, multi-
ple sclerosis, Alzheimers, Huntingtons, and Parkinsons
diseases [9,189192]. Pharmacological inhibition of FAAH
is antinociceptive in models of acute and inflammatory
pain. Furthermore, inhibition of FAAH and MAGL
reduces neuropathic pain through distinct receptor
mechanisms of action and presents viable targets for
the development of analgesic therapeutics [159]. The
site- and event-specific character of the pharmacological
inhibition of endocannabinoid-deactivating enzymes
such as FAAH and MAGL may offer increased selectiv-
ity with less risk of the undesirable side effects that have
been observed with CB receptor agonists capable of acti-
vating all accessible receptors indiscriminately [46, 47].
The broad distribution of CB1 receptors in the brain
underpins both their therapeutic effects, such as analge-
sia, as well as their side effects. Several studies have dem-
onstrated analgesic effects of CB2 receptor agonists in
models of acute and chronic pain. Peripheral antinoci-
ception without CNS effects, mediated by the ES, is con-
sistent with the peripheral distribution of CB2 receptors.
More specific drugs acting selectively on peripheral CB2
receptors, and enzyme inhibitors preventing the break-down of endocannabinoids, offer a potential to separate
the analgesic effects from the undesirable side effects of
the drug and point to a mainstream role of cannabinoid
medicines in the management of pain.
Over the last decades, numerous studies have revealed
several secrets of the ES [193,194]. Although, further
information is still needed before the ES is completely com-
prehended, pharmacological modulation of the ES seems,
nowadays, a viable target that will pave the way for the
therapeutic intervention at a wide spectrum of diseases.
A B B R E V I A T I O N S
2-AG 2-arachidonoylglycerol
2-AGE 2-arachidonoylglyceryl ether, noladin ether
ACC anterior cingulate cortex
AEA anandamide, N-arachidonoylethanolamine
APC antigen-presenting cells
CB1/CB2 receptors cannabinoid 1/cannabinoid 2
receptors
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CBD cannabidiol
CBN cannabinol
CCI chronic constriction injury
CNS central nervous system
COX cyclo-oxygenase
CYP cytochrome P450
DAG diacylglycerol
DAGL diacylglycerol lipase
DRG dorsal root ganglion
DSE depolarization-induced suppression of excitation
DSI depolarization-induced suppression of inhibition
ERK extracellular signal-regulated kinase
ES endocannabinoid system
FAAH fatty acid amide hydrolase
FAK focal adhesion kinase
GABA gamma-aminobutyric acid
IL interleukin
MAGL monoacylglycerol lipase
MAPK mitogen-activated protein kinase
NADA N-arachidonoyldopamine
NAE N-acylethanolamine
NAPE N-arachidonoylphosphatidyl-ethanolamine
NAPE-PLD NAPE-selective phospholipase D
NF-jB nuclear factor jB
NK natural killer (cells)
nNOS neuronal nitric oxide synthase
NO nitric oxide
OAE O-arachidonoylethanolamine, virodhamine
OEA oleoyl ethanolamide
PAG periaqueductal grayPC phosphatidylcholine
PEA palmitoyl ethanolamide
PE phosphatidylethanolamine
PK protein kinase
ROS reactive oxygen species
RVM rostral ventrolateral medulla
TNF-a tumor necrosis factor-a
TRPV1 transient receptor potential vanilloid 1
D9-THC D9-tetrahydrocannabinol
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