Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring
The endocannabinoid (eCB) system is a complex neuromodulatory system consisting of two classical receptors, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), their endogenous ligands named endocannabinoids, and enzymes responsible for their synthesis and degradation. This system can modulate both inhibitory and excitatory synapses in a short- or long-lasting manner. They mostly act through a retrograde mechanism in which the postsynaptic on demand release of eCBs will lead to a presynaptic CB1R activation in order to reduce transmitter release [
In recent years, the role of eCBs in visual function has been intensely studied. Recent reports suggest that the eCB system could play an instrumental role at all levels of the visual system. The vast majority of these studies focused on the effects of eCBs on adult retinal functions and only a few investigated the effects of cannabinoids on visual perception.
Reports showed that Δ9-tetrahydrocannabinol (THC) increased the recovery time from bright foveal glare by several seconds [
It is well established that marijuana consumption induces vasodilatation in conjunctiva noticeable by a reddish color change in the eyes and a reduction in intraocular pressure [
The two major eCBs (AEA and 2-AG) are present in the retina of adult rodents [
Endocannabinoid levels in the adult retina of various species.
Endocannabinoids | Concentration (pmol/g) | Species |
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2-arachidonoyl glycerol (2-AG) | 2,970 |
Rat [ |
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Anandamide (AEA) | Under detection level |
Rat [ |
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Palmitoylethanolamide (PEA) | 130 |
Rat [ |
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Oleoylethanolamide (OEA) | 55 | Rat [ |
The content of eCBs varies in certain disease states, suggesting the importance of eCBs in maintaining ocular homeostasis. For instance, 2-AG levels decrease in the ciliary body of patients with glaucoma [
CB1R was extensively studied in the retina of various species using techniques such as
Cannabinoid receptor type 1 protein distribution in the adult retina of various species.
Retinal cells | |
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Photoreceptors | Expression in the inner [ |
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Horizontal cells | Expression in the membrane but not in dendrites [ |
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Bipolar cells | Expression in the dendrites, cell body, and axons of rod bipolar cells [ |
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Amacrine cells | Expression in amacrine cells, including GABAergic amacrine cells [ |
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Inner plexiform layer | Unspecified expression in the IPL [ |
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Ganglion cells | Expression in the cell body and fibers [ |
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Müller cells | Absence of expression [ |
Schematic illustration representing the organization of the mouse retina. Rod (R) and cone (blue/C) photoreceptors have their cell bodies in the outer nuclear layer (ONL) and extend inner (IS) and outer (OS) segments. Photoreceptors axons synapse in the outer plexiform layer (OPL) with horizontal (yellow/H) and bipolar (magenta/RBC-CBC) cells. The inner nuclear layer (INL) also contains amacrine (red/A) and Müller cells (M). Bipolar cells synapse to amacrine and ganglion (blue/G) cells in the inner plexiform layer (IPL). Ganglion cell axons form the optic nerve in the ganglion cell layer (GCL) and carry signals to the brain.
Schematic illustration representing the distribution of CB1R in the adult retina of several species. CB1R expression was demonstrated in dark gray retinal cells, while CB1R presence was noted in light gray retinal layers without precise localization. OS, outer segments of photoreceptors; IS, inner segments of photoreceptors; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cones; R, rods; H, horizontal cells; CBC, cone bipolar cells; RBC, rod bipolar cells; A, amacrine cells; G, ganglion cells; M, Müller cells.
The cannabinoid receptor type 2 (CB2R) distribution in the retina has been less extensively studied than CB1R. This could be explained in part by the lack of specific markers for CB2R [
Cannabinoid receptor type 2 protein distribution in the adult retina.
Retinal cells | |
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Photoreceptors | Expression in the outer and inner segments of cones [ |
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Horizontal cells | Expression at the membrane of the soma and in horizontal cells, dendrites [ |
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Bipolar cells | Expression in the membrane of the soma and axons of rod bipolar cells [ |
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Amacrine cells | Expression in some subtypes [ |
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Ganglion cells | Expression in the soma [ |
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Müller cells | Absence of expression at the membrane of the soma, in Müller cells, inner and outer processes [ |
Schematic illustration showing the expression of CB2R in the adult retina of several species. CB1R expression was demonstrated in dark gray retinal cells, while CB2R presence was noted in light gray retinal layers without precise localization. OS, outer segments of photoreceptors; IS, inner segments of photoreceptors; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cones; R, rods; H, horizontal cells; CBC, cone bipolar cells; RBC, rod bipolar cells; A, amacrine cells; G, ganglion cells; M, Müller cells. Scale bar: 20
In recent years, the G-protein coupled receptor 55 (GPR55) was suggested to act as a cannabinoid receptor since it interacts with AEA and THC [
Another cannabinoid-like receptor present in the retina is the transient receptor potential vanilloid 1 (TRPV1), which binds eCBs such as AEA and N-arachidonoyl dopamine [
The G-protein coupled receptor 18 (GPR18) is activated by N-arachidonoyl glycine (NAGly), the endogenous metabolite of AEA, and is suggested to be the “abnormal-CBD” (Abn-CBD) receptor [
Furthermore, there is growing evidence that the intracellular peroxisome proliferator-activated receptors (PPARs) are the targets of cannabinoid ligands. PPARs belong to a family of nuclear receptors comprising three isoforms:
The first retinal localization of the enzymes responsible for 2-AG synthesis was recently reported. Diacylglycerol lipase alpha (DAGL
The hydrolyzing enzyme FAAH, which is responsible for the degradation of AEA, is localized in the retina of mice [
The metabolizing enzyme MAGL is expressed in the mouse and rat retina. It was first detected in the OPL, IPL, and GCL [
The expression of the metabolizing ABHD6, a serine hydrolase [
For now, no studies have revealed the presence of ABHD12 in the retina [
As CB1R is the most abundant GPCR in the CNS, it is not surprising that the eCB system is also present in several visual brain regions beyond the retina. For instance, CB1R is expressed throughout the dorsal lateral geniculate nucleus (dLGN) of vervet monkeys, with a prominent labeling in the magnocellular layers [
In the retina, cannabinoids inhibit the release of various neurotransmitters. Indeed, CB1R agonists decrease the release of [3H]-noradrenaline and [3H]-dopamine in the guinea pig [
In recent years, epithelial cells have been shown to be of importance in several models of pathology induced in cultured RPE cells. In one study, high glucose-mediated apoptosis in ARPE-19 RPE cells was reduced by the overexpression of FAAH, via CB1R blockade and via CB1R siRNA transfection, demonstrating a therapeutic potential for FAAH modulation in diabetic retinopathy [
Different effects on rod and cone photoreceptors have been reported for the salamander and goldfish following WIN55,212-2 addition, with a potential biphasic response based on concentration for the goldfish. Delayed rectifier currents (
As for photoreceptors, Straiker and Yazulla’s groups were the first to describe a cannabinoid-mediated effect in the salamander and the goldfish, respectively [
WIN55212-2 also inhibits the enhancement in
The neuroprotective effects of endogenous and synthetic cannabinoids on the viability of amacrine cells were studied using an
It has been reported that WIN55,212-2, AEA, the selective CB1R agonist arachidonoyl-2-chloroethylamide (ACEA), and the CB2R agonist CB65 inhibit
In addition to their effect at the level of ionic channels, eCBs, via CB1R, have neuroprotective properties. In fact, blockade of FAAH produces neuroprotective effects on RGCs in a rat model of optic nerve axotomy through a CB1R-mediated mechanism, which was gradually lost in aging animals [
Various TRP channels can be activated by tactile and pressure stimuli, including TRPV channels [
So far, few studies have looked at the effects of eCBs on central visual areas processing. CB1R activation alters spontaneous and visual activity in the rat dLGN, increasing the spontaneous bursting and oscillatory activity [
As shown in other systems, eCBs are well known modulators of synaptic transmission and neuronal plasticity, mostly via presynaptic inhibitory mechanisms. The impact of the eCB system during CNS development has been documented in the last decade. The eCB system regulates the proliferation, migration, specification, and survival of neural progenitors [
CB1R mRNA is expressed in the rat retina as early as embryonic age 13 (E13), which is a good indicator of its possible developmental implication [
The TRPV1 receptor is also present in the rat retina from E19 onto adulthood [
No studies have yet reported the expression of GPR18 in the developing retina. Ongoing projects from our group have so far shown that GPR55 mRNA and protein are expressed in the retina of newly born mice, more specifically in RGCs [
Only two studies reported the functional impact of cannabinoids on retinal development. CB1R and CB2R specific agonists induce a collapse of the growth cone of RGC axon and decrease axon growth [
As we have reported in this review, CB1R and CB2R are both present in various retinal tissue where they modulate, in the most part via retrograde signaling, neurotransmitter release and where they inhibit potassium and calcium currents. These effects can thus modulate visual activity as early as the retina level. More studies are obviously needed to assess to what extent a cannabinoid-mediated modulation in the retina could impact visual perception. This is especially true given that cannabinoid receptors are present in most retinal cell types. As cannabinoids are also present in the visual cortex (including areas beyond V1 and V2), as well as subcortical regions such as the LGN, it may well be that cannabinoids modulate visual perception at each level of visual system hierarchy.
The ability of the eCB system to induce various changes in plasticity in central visual areas is now well described (for review, see [
Endocannabinoids constitute one of the newest neuromodulators found in neural and nonneural tissues throughout the body. Their wide expression in the nervous system and peripheral organ systems highlights the range of their actions and their potential in therapeutic applications. Strong evidence now suggests a wide distribution of eCBs, receptors, and enzymatic machinery in key structures of the visual system, including a strong presence in the retina. Although no clear picture can ascertain the specific effects cannabinoids can have in the retina itself, or the visual system as a whole, various mechanisms in specific cellular structures of the retina have now been reported. The cannabinoid system also appears to have several roles in neuronal survival and apoptosis in the retina and could be linked with many other ocular disorders. However, their specific mechanisms in retinal development, neuroplasticity, and neuroprotection need to be more thoroughly investigated.
The authors confirm that there is no conflict of interests regarding the publication of this paper.