CB1, a cannabinoid receptor enriched in neuronal tissue, was found in high concentration in retinas of rhesus monkey, mouse, rat, chick, goldfish, and tiger salamander by using a subtype-specific polyclonal antibody. Immunolabeling was detected in the two synaptic layers of the retina, the inner and outer plexiform layers, of all six species examined. In the outer plexiform layer, CB1 was located in and͞or on cone pedicles and rod spherules. Labeling was detected in some amacrine cells of all species and in the ganglion cells and ganglion cell axons of all species except fish. In addition, sparse labeling was found in the inner and͞or outer segments of the photoreceptors of monkey, mouse, rat, and chick. Using GC͞MS to detect possible endogenous cannabinoids, we found 3 nmol of 2-arachidonylglycerol per g of tissue, but no anandamide was detectable. Cannabinoid receptor agonists induced a dramatic reduction in the amplitude of voltage-gated L-type calcium channel currents in identified retinal bipolar cells. The presence and distribution of the CB1 receptor, the large amounts of 2-arachidonylglycerol found, and the effects of cannabinoids on calcium channel activity in bipolar cells suggest a substantive role for an endogenous cannabinoid signaling system in retinal physiology, and perhaps vision in general. Cannabinoids are the principal psychoactive component of marijuana and hashish, acting on an intrinsic G proteincoupled receptor in nervous tissue that normally responds to endogenous ligands such as anandamide (arachidonylethanolamide, or AEA) (1). Despite considerable recent progress, the mechanisms of cannabinoid action in the body remain poorly understood, particularly in the case for the role of cannabinoids in vision. Published research and case studies as well as a host of anecdotal reports describe numerous effects on visual perception including altered thresholds of light detection and glare recovery (2-4). The possible loci within the retina and͞or brain responsible for these perceptual changes are unknown. Our report may identify one of the major sites responsible for the alterations in the visual world of some cannabinoid users.The first cannabinoid receptor, CB1, was cloned in 1990 (5). Since then the CB1 receptor has been found to be expressed at high levels in specific brain regions (6). Putative endogenous ligands have been identified: anandamide (1) and 2-arachidonylglycerol (2-AG) (7). Endogenous cannabinoids have been shown to produce effects on memory, signaling pathways, and the perception of pain, (8-14) and have even been found to inhibit dopamine release in the leech (15), implying an inveterate history as a neuromodulatory system. Recent evidence suggests that cannabinoid receptors are found in the retina, with one study demonstrating an anandamide-induced inhibition of dopamine release (16) and another study showing expression of CB1 mRNA through in situ labeling in embryonic rat retina (17). Recently, Porcella et al. (18) have found mRNA for CB1 in retina, by using reverse transcr...

Bipolar-cell axon terminals receive direct synaptic input from amacrine-cell processes, suggesting a possible pathway for modulation of transmitter release. In retinal slices, bath-applied baclofen, a y-aminobutyrate type B (GABAB) receptor agonist, reduced a patch-clamp-recorded L-type calcium channel current in a population of bipolar cells with axon terminals that ramify along the midline of the inner plexiform layer. Lucifer yellow staining revealed that this current was found only in bipolar cells that retain axon terminals and their associated telodendria, suggesting that the current is generated at the terminal and also possibly modulated there. T-type calcium currents were found in all bipolar cells, including those without axon terminals, but were not modulated by baclofen. The baclofen-induced !eduction of calcium current was enhanced by guanosine 5'-[y-thioltriphosphate and eliminated by guanosine 5'-[13-thioldiphosphate added to the cytoplasm by the patch recording electrode, suggesting that the GABAAB receptors act through a guanine nucleotide-binding regulatory protein (G protein). Baclofen also reduced an excitatory synaptic input to a population of amacrine cells with processes that ramify along the midline of the inner plexiform layer-cells probably postsynaptic to the bipolar terminals. This suggests that GABAB receptors modulate not only the calcium current but also transmitter release by a pathway involving G proteins and L-type calcium channels.

As an example of the burgeoning importance of stem cell therapy, this past month the California Institute for Regenerative Medicine (CIRM) has approved $70 million to create a new network of stem cell clinical trial centers. Much work in the last decade has been devoted to developing the use of autologous and allogeneic adult stem cell transplants to treat a number of conditions, including heart attack, dementia, wounds, and immune system-related diseases. The standard model teaches us that adult stem cells exists throughout most of the body and provide a means to regenerate and repair most tissues through replication and differentiation. Although we have often witnessed the medical cart placed in front of the scientific horse in the development of stem cell therapies outside of academic circles, great strides have been made, such as the use of purified stem cells1 instead of whole bone marrow transplants in cancer patients, where physicians avoid re-injecting the patients with their own cancer cells.2 We most often think of stem cell therapy acting to regenerate tissue through replication and then differentiation, but recent studies point to the dramatic effects adult stem cells exert in the repair of various tissues through the release of paracrine and autocrine substances, and not simply through differentiation. Indeed, up to 80% of the therapeutic effect of adult stem cells has been shown to be through paracrine mediated actions.3 That is, the collected types of molecules released by the stem cells, called the secretome, or stem cell released molecules (SRM), number in the 100s, including proteins, microRNA, growth factors, antioxidants, proteasomes, and exosomes, and target a multitude of biological pathways through paracrine actions. The composition of the different molecule types in SRM is state dependent, and varies with cell type and conditions such as age and environment.