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:

[email protected]

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

2012 The Authors Fundamental and Clinical Pharmacology 2012 Societe Francaise de Pharmacologie et de Therapeutique

64 Fundamental & Clinical Pharmacology 27 (2013) 6480

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.



66 P. Zogopoulos et al.


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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





10/17

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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