Cannabinoid receptors and their ligands constitute an endogenous signaling system that is found throughout the body, including the eye. This system can be activated by Δ 9 -tetrahydrocannabinol, a major drug of abuse. Cannabinoids offer considerable therapeutic potential in modulating ocular immune and inflammatory responses and in regulating intraocular pressure. The location of cannabinoid receptors 1 (CB 1 ) in the retina is known, but recently a constellation of proteins has been identified that produce and break down endocannabinoids (eCBs) and modulate CB 1 function. Localization of these proteins is critical to defining specific cannabinoid signaling circuitry in the retina.Here we show the localization of diacylglycerol lipase α and β (DGLα/β), implicated in the production of the eCB 2-arachidonoyl glycerol (2-AG); monoacylglycerol lipase (MGL) and α/β-hydrolase domain 6 (ABHD6), both implicated in the breakdown of 2-AG; cannabinoid receptor interacting protein 1a (CRIP1a), a protein that may modulate CB 1 function; Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) which have been shown to break down the eCB anandamide and related acyl amides. In our most prominent finding, DGLα is present in post-synaptic Type 1 OFF cone bipolar cells juxtaposed to CB 1 -containing cone photoreceptor terminals. Interestingly, CRIP1a is reliably presynaptic to DGLα, consistent with a possible role in cannabinoid signaling, NAAA is restricted to retinal pigment epithelium (RPE), while DGLβ is limited to retinal blood vessels. These results taken together with previous anatomic and functional studies define specific cannabinoid circuitry likely to modulate eCB signaling at the first synapse of the retina as well as in the inner plexiform layer (IPL).

BACKGROUND AND PURPOSECannabinoids such as D 9 -tetrahydrocannabinol, the major psychoactive component of marijuana and hashish, primarily act via cannabinoid CB1 and CB2 receptors to produce characteristic behavioural effects in humans. Due to the tractability of rodent models for electrophysiological and behavioural studies, most of the studies of cannabinoid receptor action have used rodent cannabinoid receptors. While CB1 receptors are relatively well-conserved among mammals, human CB1 (hCB1) differs from rCB1 and mCB1 receptors at 13 residues, which may result in differential signalling. In addition, two hCB1 splice variants (hCB1a and hCB1b) have been reported, diverging in their amino-termini relative to hCB1 receptors. In this study, we have examined hCB1 signalling in neurones. EXPERIMENTAL APPROACHhCB1, hCB1a hCB1b or rCB1 receptors were expressed in autaptic cultured hippocampal neurones from CB1 -/-mice. Such cells express a complete endogenous cannabinoid signalling system. Electrophysiological techniques were used to assess CB1 receptor-mediated signalling. KEY RESULTSExpressed in autaptic hippocampal neurones cultured from CB1 -/-mice, hCB1, hCB1a and hCB1b signal differentially from one another and from rodent CB1 receptors. Specifically, hCB1 receptors inhibit synaptic transmission less effectively than rCB1 receptors. CONCLUSIONS AND IMPLICATIONSOur results suggest that cannabinoid receptor signalling in humans is quantitatively very different from that in rodents. As the problems of marijuana and hashish abuse occur in humans, our results highlight the importance of studying hCB1 receptors. They also suggest further study of the distribution and function of hCB1 receptor splice variants, given their differential signalling and potential impact on human health. LINKED ARTICLESThis article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx