Alvo Dos Cannabinoides
Alvo Dos Cannabinoides
Alvo Dos Cannabinoides
Review
been developed [3,4]. Two of these, the CB1/CB2 brain. The peripherally restricted potent, orally active
receptor agonist, D9-tetrahydrocannabinol (D9-THC; CB1/CB2 receptor agonist, ‘compound A’, has also
dronabinol; Marinol) and its synthetic analogue, been reported to display anti-hyperalgesic activity at
Nabilone (Cesamet), were approved over 25 years ago sub-cataleptic doses in a rat spinal nerve ligation
as medicines for suppressing nausea and vomiting model of neuropathic pain and to produce signs of
produced by chemotherapy. Subsequently, the use of dro- anti-hyperalgesia in the mouse formalin paw model of
nabinol as an appetite stimulant, for example in AIDS inflammatory pain [8]. Three other such compounds
patients experiencing excessive loss of body weight, are AZD1940, AZD1704 and AZ11713908, each of
was also approved. One other medicine that contains which seems to produce signs of analgesia in rodent
D9-THC, in this case together with the non-psychoactive models of acute, inflammatory and/or neuropathic
plant cannabinoid, cannabidiol, is Sativex. This was pain through the activation of peripheral cannabinoid
licensed in Canada in 2005 for the symptomatic relief of CB1 receptors when administered orally [9,10]. It is
neuropathic pain in multiple sclerosis and as an adjunctive also noteworthy that AZ11713908 generates fewer
analgesic treatment for adult patients with advanced signs of CNS side effects in a rat Irwin test than
cancer. In 2010, it was also licensed in the UK and the CB1/CB2 receptor agonist, R-(þ)-WIN55212.
Canada for the treatment of spasticity due to multiple There is evidence too that a synthetic analogue of
sclerosis and has more recently become an approved D8-THC, ajulemic acid (CT-3), may ameliorate
medicine in several other countries. Although these medi- neuropathic pain mainly by targeting cannabinoid
cines do of course all display a favourable benefit-to-risk receptors located outside the blood-brain barrier [3].
ratio, they can give rise to unwanted side effects [3–5]. Five further examples of peripherally restricted
There is currently a lot of interest in the possibility of cannabinoids that can induce antinociception in
developing medicines from compounds that inhibit the animal models are the cannabilactone, AM1710 [11];
cellular uptake and/or metabolism of endocannabinoids the 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione
when these are being released in an autoprotective derivative, compound 44 [12]; the 5-sulphonyl-
manner [1,6]. However, also attracting considerable benzimidazole derivative, compound 49 [13]; the
interest is the idea of exploiting one or other of a wide g-carboline, compound 29 [14]; and the thiadiazole,
range of pharmacological strategies expected to maxi- compound LBP1 [15]. AM1710 reduces signs of pain eli-
mize the beneficial therapeutic effects and/or minimize cited by thermal (but not mechanical) stimulation of the
the unwanted effects of drugs that activate cannabinoid rat hind paw at doses that do not produce signs of
receptors directly. It is these strategies that form the unwanted CNS side-effects [11]. Similar results were
subject of this review. obtained with LBP1 in a rat model of neuropathic pain
[15]. AM1710 and compounds 44 and 49 are CB2-
selective cannabinoid receptor agonists, whereas com-
2. DIRECT ACTIVATION OF CANNABINOID pounds 29 and LBP1 are dual CB1/CB2 receptor ligands.
RECEPTORS LOCATED OUTSIDE THE Finally, although orally administered AZD1940
BLOOD-BRAIN BARRIER displays antinociceptive activity in rat models of
It is now generally accepted, first, that many of the acute and neuropathic pain [9], results obtained in
unwanted effects of cannabinoid receptor agonists are single-dose phase-II studies indicated that it was inef-
caused by their activation of CB1 receptors located fective against acute pain induced in human subjects
within the brain and, second, that beneficial effects by capsaicin or by molar tooth extraction [16].
such as pain relief, amelioration of certain intestinal
and cardiovascular disorders, and inhibition of cancer
cell proliferation and spread can be induced by selec- 3. DIRECT ACTIVATION OF CANNABINOID
tively activating CB1 and/or CB2 receptors expressed RECEPTORS EXPRESSED BY A
outside the central nervous system [1]. This raises the PARTICULAR TISSUE
possibility of developing a peripherally restricted medi- There is a strong possibility that the benefit-to-risk ratio
cine that selectively activates cannabinoid receptors of a cannabinoid CB1 or CB1/CB2 receptor agonist
located outside the blood-brain barrier. Attention is could be markedly increased by restricting the distri-
focused particularly on the possibility of developing bution of active concentrations of this agonist to a
such medicines for pain relief. tissue that expresses cannabinoid receptors, which,
One peripherally restricted cannabinoid receptor when activated, would mediate relief from the unwanted
agonist that possesses antinociceptive activity is effects of one or more particular disorders. Two such
naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone. tissues may be skin and spinal cord, there being
This is a potent, high-efficacy, orally bioavailable CB1/ good evidence that these both contain cells that express
CB2 receptor agonist that displays significant anti- CB1 and CB2 receptors, the activation of which can
hyperalgesic activity in a rat sciatic nerve partial produce signs of analgesia or anti-hyperalgesia in
ligation model of neuropathic pain and that appears animal models of acute, inflammatory or neuropathic
to act by targeting peripheral CB1 receptors [7]. pain [3]. There is evidence too that when adminis-
Thus, its antihyperalgesic effect can be attenuated by tered intrathecally, the CB1/CB2 receptor agonist,
a CB1-selective antagonist (SR141716A), but not by R-(þ)-WIN55212, can induce spinal CB1 and CB2
a CB2-selective antagonist (SR144528); it can produce receptor-mediated signs of relief from bone-tumour-
this antinociceptive effect without inducing a behav- related pain [17], and also antinociception in a rat
ioural effect thought to be mediated by central CB1 formalin paw model of inflammatory pain, although
receptors (catalepsy), and it does not readily enter the not in the rat hot plate model of acute pain [18].
Phil. Trans. R. Soc. B (2012)
Review. Targeting the endocannabinoid system R. G. Pertwee 3355
In addition, results obtained from experiments with 5. ACTIVATING CANNABINOID CB2 RECEPTORS
mice indicate that R-(þ)-WIN55212 can act through Significant attention is currently being directed at the
CB1 and CB2 receptors to reduce signs of hyperalgesia possibility of developing medicines from compounds
without also inducing catalepsy when it is injected that can activate CB2 receptors at doses that induce
into tumour-bearing hind paws [19], and that the little or no CB1 receptor activation. This has been trig-
CB2-selective agonist, JWH-015, can induce a CB2- gered by the evidence that many of the adverse effects
receptor-mediated reduction in bone-cancer-related induced by mixed CB1/CB2 receptor agonists result
pain caused by implantation of NCTC2472 fibrosar- from CB1 rather than from CB2 receptor activation,
coma cells into the femur [20]. It has been found too and that CB2-selective agonists have a number of impor-
that intraplantar injection of 2-arachidonoyl glycerol tant potential therapeutic applications. These include
can induce CB2 receptor-mediated relief from hyperal- the relief of various kinds of pain and the treatment of
gesia in a murine model of human metastatic bone pruritus, of certain types of cancer, of cough and of
cancer pain in which fibrosarcoma cells are injected some neurodegenerative, immunological, inflamma-
into and around the calcaneus bone of the left hind tory, cardiovascular, hepatic, renal and bone disorders
paw of each animal, and in which CB2 receptor (table 1). There is also evidence, first, that CB2 receptor
expression increases in non-neuronal cells in the plantar activation can ameliorate neuroinflammation by pro-
skin of the tumour-bearing paw [21]. Other cannabi- tecting the blood-brain and blood-spinal cord barriers
noid receptor agonists that have been found to reduce [67,68]), and second that activation of these receptors
signs of hyperalgesia in this experimental model include can reduce inflammation following spinal cord injury
AM1241, which is CB2-selective and was antagonized by lowering the expression of toll-like receptors [68]).
by the CB2-selective antagonist, AM630, but not Importantly, none of the CB2-selective agonists that
by the CB1-selective antagonist, AM281, and arachido- have been developed to-date are completely CB2-specific.
nylcyclopropylamide, which is CB1-selective and As a result, they are expected to display CB2-selectivity
was antagonized by AM281, but not by AM630 only within a finite dose range and to target CB1 receptors
[22]. Experiments with mice have also shown that as well when administered at a dose that lies above this
R-(þ)-WIN55212 can reduce nociception in the radi- range. Indeed, there is evidence from experiments with
ant heat tail-flick test when it is applied topically to the CB1 wild-type and knockout mice that although some
tail at a dose that did not impair rotarod performance CB2-selective agonists can reduce spasticity in an auto-
[23,24]. It could well be, therefore, that by applying a immune encephalomyelitis model of multiple sclerosis,
cannabinoid receptor agonist directly to the skin, it this depends on their ability to activate CB1 receptors at
would be possible to relieve pain that is restricted to doses above those at which they activate CB2 receptors
one or more specific regions of the body surface without [69]. Evidence has also been obtained first, that cannabi-
also provoking major off-target cannabinoid receptor- noid receptor-dependent alleviation of mechanical
mediated effects. Further support for this possibility allodynia that is induced in mice by brachial plexus avul-
comes from experiments performed with human volun- sion appears to be mainly CB2-mediated in the initial
teers, which showed that hyperalgesia induced by phase but both CB1- and CB2-mediated in the late
capsaicin application to the skin, and the perception of phase [32], and second, that in a mouse collagen-induced
itch induced by cutaneous administration of histamine, arthritis model, although signs of arthritis are reduced by
could both be decreased by pretreatment with the CB1/ prolonged CB2 but not prolonged CB1 receptor acti-
CB2 receptor agonist, HU-210, when this was adminis- vation, thermal hyperalgesia is reduced by acute CB1
tered by skin patch or dermal microdialysis at a dose that but not by acute CB2 receptor activation [70]. In addition,
did not produce psychological side effects [25,26]. Also it is likely that pharmacological targets other than CB2 or
meriting further investigation is the possibility that CB1 receptors contribute to sought-after or unwanted
topical application of a cannabinoid CB1 receptor ago- effects of CB2-selective agonists, there being evidence,
nist to one or more areas of the skin might be an for example, that some but not all such agonists can
effective way of treating (or even preventing) melanoma activate GPR55 and/or modulate activation of this deor-
induced by ultraviolet irradiation [27]. phanized receptor by L-a-lysophosphatidylinositol [71].
It is noteworthy too that CB2 receptors seem to increase
survival rate in a model of mild sepsis but to reduce survi-
4. ACTIVATING UPREGULATED val rate in a model of more severe sepsis, that CB2 receptor
CANNABINOID RECEPTORS activation appears both to exaggerate and to block
Some disorders seem to trigger a ‘protective’ upregulation inflammatory responses in a model of allergic contact der-
of certain cannabinoid CB1 or CB2 receptors that, when matitis, and that some inflammatory responses that seem
activated, can slow the progression of these disorders or to be aggravated by CB2 receptor agonists are alleviated
ameliorate their symptoms [1,3]. As discussed in greater by CB2 receptor inverse agonists [41].
detail elsewhere [3], the occurrence of such protective
upregulation raises the possibility that for the treatment
of at least some disorders, a partial cannabinoid receptor 6. POTENTIAL ADJUNCTIVE STRATEGIES FOR
agonist—for example, D9-THC or cannabinol—might CANNABINOID RECEPTOR ACTIVATION
display a greater benefit-to-risk ratio than a higher efficacy There is good evidence that it may be possible to
agonist such as CP55940. This is because the extent to improve the benefit-to-risk ratio of a cannabinoid
which the size the maximal effect of an agonist increases receptor agonist such as D9-THC, CP55940, R-(þ)-
in response to any upregulation of its receptors is inversely WIN55212 or HU-210 for the management of pain
related to the efficacy of that agonist. by administering it together with a second drug.
Phil. Trans. R. Soc. B (2012)
3356 R. G. Pertwee Review. Targeting the endocannabinoid system
Table 1. Examples of potential therapeutic targets for selective CB2 receptor agonists.
Thus, for example, additive or synergistic interactions — HU-210 and the non-steroidal anti-inflammatory
resulting in antinociception have been reported to drug, acetylsalicylic acid, co-administered systemi-
occur in the rat formalin paw model of inflammatory cally, in the rat hot plate model of acute pain [76];
pain between — D9-THC and an opioid such as morphine, codeine
or fentanyl in mouse, rat, guinea pig and monkey
— intraperitoneal D9-THC and morphine [72]; models of acute or arthritic pain [79– 89];
— intrathecal R-(þ)-WIN55212 and an intrathecally — CP55940 and the a2-adrenoceptor agonist, dexme-
administered a2-adrenoceptor agonist (clonidine), detomidine, in the mouse hot plate and tail flick
cholinesterase inhibitor (neostigmine) or local models of acute pain [83];
anaesthetic (bupivicaine) [73,74]; — CP55940 and the N-methyl-D-aspartate (NMDA)
— anandamide and the cyclooxygenase inhibitor, receptor antagonist, (–)-6-phosphonomethyl-deca-
ibuprofen, administered by intraplantar injection hydroisoquinoline-3-carboxylic acid (LY235959),
[75]; and in the mouse hot plate test [90]; and
— HU-210 and the non-steroidal anti-inflamma- — R-(þ)-WIN55212, given by intracerebroven-
tory drug, acetylsalicylic acid, co-administered tricular or intraplantar injection, and a selective
systemically [76]. agonist for the neuropeptide FF1 or FF2 receptor,
injected intracerebroventricularly, in mouse
Additive or synergistic interactions resulting in antino- models of acute pain [91].
ciception have also been found to occur between
— low-dose R-(þ)-WIN55212 and a cyclooxygenase-2 Importantly, evidence has been obtained through
inhibitor, NS-398, co-administered intracisternally, the construction of isobolograms that of the above
for the attenuation of nociceptive scratching behav- interactions, those between R-(þ)-WIN55212 and
iour induced in rats by formalin injection into the clonidine, neostigmine or bupivicaine [73,74] as well
temporomandibular joint of the jaw [77]; as those between anandamide and ibuprofen [75],
— R-(þ)-WIN55212 and the non-steroidal anti- D9-THC and an opioid [81,83,86], CP55940 and dex-
inflammatory drug, ketorolac, co-administered sys- medetomidine [83] and CP55940 and LY235959
temically, for the attenuation of nociception in a [90], are all synergistic rather than just additive in
mouse model of inflammatory visceral pain, nature. A synergistic antinociceptive interaction has
although not in the mouse tail flick model of also been reported to occur between the CB1-selective
acute pain [78]; agonist, arachidonylcyclopropylamide, and the
Phil. Trans. R. Soc. B (2012)
Review. Targeting the endocannabinoid system R. G. Pertwee 3357
Table 2. Examples of additive or synergistic interactions observed in vivo between cannabinoid receptor agonists and non-
cannabinoid receptor ligands in animal models of certain disorders.a ACEA, arachidonyl-20 -chloroethylamide; 8-OH-DPAT,
8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide; i.p., intraperitoneal; i.v., intravenous; s.c., subcutaneous.
cannabinoid receptor
disorder and measured effect agonist co-administered compound reference
anxiety or depression
anxiolytic effects in mouse elevated plus- R-(þ)-WIN55212 (i.p.) diazepam (i.p.) [98]
mazec and mouse hole-board test
anxiolytic effects in mouse light-dark box, low-dose D9-THC (i.p.) low-dose nicotine (s.c.) [99,100]
open-field test and elevated plus-maze
anxiolytic effect in rat elevated plus-maze low-dose D9-THC (i.p.) low dose of the 5-HT1A [101]
receptor-selective agonist,
8-OH-DPAT (i.p.)
antidepressant effect in rat forced swim low-dose CP55940 (i.p.) low-dose imipramine (i.p.) [102]
test
epilepsy
anticonvulsant effect on mouse low-dose of the CB1- low-dose naltrexone (i.p.) [103]
pentylenetetrazole-induced clonic or selective agonist, ACEA
tonic-clonic seizures (i.p.)
anticonvulsant effect on mouse low-dose R-(þ)-WIN ethosuximide, phenobarbital or [104]
pentylenetetrazole-induced clonic 55212 (i.p.) valproate (i.p.)
seizures
anticonvulsant effect on mouse maximal low-dose R-(þ)-WIN55212 carbamazepine, phenytoin, [105]
electroshock-induced seizures (i.p.) phenobarbital or valproate (i.p.)
anticonvulsant effect on mouse maximal low-dose of the CB1- phenobarbital (i.p.) [106]
electroshock-induced seizures selective agonist, ACEA
(i.p.)
anticonvulsant effect on mouse low-dose R-(þ)-WIN55212 diazepam (i.p.) [107]
electroshock-induced seizures (i.p.)
haemorrhagic shock or glaucoma
increased survival time in a rat model of D8-THC (i.v.) cyclooxygenase-2 inhibitor, NS-398 [108]
haemorrhagic shock (i.v.)
reduction of rat intraocular pressure low-dose R-(þ)-WIN55212 low-dose abnormal-cannabidiol or [109]
(i.p.) cannabigerol-dimethyl heptyl
(topical)
cancer or chemotherapy-induced vomiting
reduction of glioma xenograft growth in low-dose D9-THC low-dose temozolomide [110]
nude mice (peritumorally) (peritumorally)b
inhibition of vomiting and retching low-dose D9-THC (i.p.) low dose of the 5-HT3 receptor [111]
induced by cisplatin in house musk antagonist, ondansetron (i.p.)
shrews
a
See introduction to this section for antinociceptive interactions.
b
Low-dose temozolomide also exerted a strong anti-tumoral effect in combination with a low-dose mixture of D9-THC and the
non-psychoactive phytocannabinoid, cannabidiol.
c
Isobolographic analysis indicated this interaction to be synergistic.
CB2-selective agonist, AM1241, in a mouse model of the m-opioid receptor agonist, piritramide, in patients
cancer pain following intraplantar coadministration suffering from acute post-operative pain [95] or between
of these two compounds [22]. This is of interest D9-THC and morphine in human volunteers subjected
since it raises the possibility that, for at least some to noxious electrical or thermal stimulation of the skin
kinds of pain, a mixed CB1/CB2 agonist may be more or to painful digital pressure [96,97]. However, together
effective as an analgesic medicine than a CB1- or (but not separately), these drugs did reduce the affective
CB2-selective agonist. response to cutaneous thermal stimulation [97].
Results from clinical studies with patients experien- Evidence that certain potentially beneficial effects of
cing chronic non-cancer pain have also provided a cannabinoid receptor agonist other than pain relief can
evidence that cannabinoid receptor agonists can be enhanced by administering it together with one or
enhance opioid-induced analgesia [92,93] and that other of a set of non-cannabinoid receptor ligands
inhaled vapourized cannabis can augment the analgesic has also emerged from in vivo animal experiments
effect of the opioids, morphine and oxycodone in (table 2). It should be noted that the anticonvulsant
patients experiencing various kinds of chronic pain with- interactions between R-(þ)-WIN55212 and ethosuxi-
out inducing any unacceptable adverse events [94]. mide or valproate that are referred to in table 2 were
In contrast, no synergistic or additive antinociceptive probably at least partly pharmacokinetic in nature
interaction has been detected between D9-THC and [104], whereas those between R-(þ)-WIN55212 or
Phil. Trans. R. Soc. B (2012)
3358 R. G. Pertwee Review. Targeting the endocannabinoid system
come almost entirely from preclinical research. class: antinociception without central nervous system
Consequently there is now an urgent need, first, side-effects. Pharmacol. Biochem. Behav. 98, 493 –502.
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