Extending the scope of the previous studies, first we investigated whether astrocytes that carry CB 1-Rs also express DGLα.įirst, we obtained sections of lamina I-II of the rat spinal dorsal horn and carried out triple immunostainings for glial fibrillary acidic protein (GFAP a marker for astrocytes), CB 1-Rs and DGLα. Therefore, in the present study, we investigated whether spinal astrocytes can release 2-AG in response to activation of their CB 1-Rs.Īstrocytes in the superficial spinal dorsal horn express CB 1-Rs and DGLα in close proximityĪlmost half and one third of the astrocytic profiles show positive immunostaining for CB 1-R and DGLα, respectively, in the superficial spinal dorsal horn 19, 26. Filling up these gaps in our knowledge seems particularly important given that endocannabinoid mediated neuron-astrocyte-neuron signaling appears to be crucial in many functions of the central nervous system including pain processing in the spinal dorsal horn. In addition, though activation of CB 1-Rs on astrocytes leads to Ca 2+ mobilization 16, 17 and Ca 2+ transients may evoke the production of 2-AG 22, 23, 24, 2-AG release from astrocytes evoked by CB 1-R activation has never been demonstrated. The synthesis of 2-AG in astrocytes can be evoked by ATP or endothelin 20, 22, 23, requires a sustained increase in the intracellular calcium concentration ( i) and the subsequent activation of the PLC-diacylglycerol lipase alpha (DGLα, the synthesizing enzyme for 2-AG) pathway 22, 23, 24.Īlthough astrocytes express CB 1-Rs and DGLα 19, 25, 26, the spatial co-expression of these proteins in astrocytes has never been investigated. It has also been shown that astrocytes have the potential to produce one of the best-known endogenous CB 1-R agonist 2-arachidonoylglycerol (2-AG) 20, 21, 22. Navarrate and Araque showed that in the hippocampus endocannabinoids released by neurons activate CB 1-Rs on astrocytes, which - in contrast to activation of CB 1-Rs on neurons - leads to phospholipase C (PLC)-dependent Ca 2+ mobilization from internal stores and a consecutive release of glutamate that activates NMDA receptors in adjacent pyramidal neurons 16, 17. It is well established that in addition to neurons, astrocytes also express cannabinoid type-1 receptors (CB 1-R) both in the brain 16 and spinal cord 18, 19. In turn, astrocytes release neuroactive substances called gliotransmitters, like glutamate, D-serine and ATP 10, which modulate neuronal excitability and synaptic transmission 11, 12, 13, 14.Įndocannabinoids are also implicated in this bidirectional signaling 15, 16, 17. Astrocytes express various neurotransmitter receptors, such as glutamatergic and purinergic receptors 7, the activation of which leads to the mobilization of Ca 2+ from intracellular stores 8, 9. Since then, many details of a bidirectional communication between astrocytes and neurons has been demonstrated 4, 5, 6. However, the discovery that Ca 2+ transients in astrocytes are coupled to the enhancement or depression of neuronal activity has led to the recognition that astrocytes may play a substantial role in neural information processing 1, 2, 3. The results provide evidence for a novel cannabinoid induced endocannabinoid release mechanism in astrocytes which broadens the bidirectional signaling repertoire between astrocytes and neurons.Īstrocytes were long thought to play only a supporting role in the central nervous system. Finally, we provide evidence that the evoked Ca 2+ transients lead to the production of 2-arachidonoylglycerol in cultured astrocytes. We also demonstrate that activation of CB 1-Rs induces a substantial elevation of intracellular Ca 2+ concentration in astrocytes. Here we show that rat spinal astrocytes co-express CB 1-Rs and the 2-arachidonoylglycerol synthesizing enzyme, diacylglycerol lipase-alpha in close vicinity to each other. However, no relationship between CB 1-R activation and 2-arachidonoylglycerol production has ever been demonstrated. It has also been documented that astrocytes have the potential to produce the endocannabinoid 2-arachidonoylglycerol, one of the best known CB 1-R agonist. It has been reported that some astrocytes express the cannabinoid type 1 receptor (CB 1-R), the activation of which is leading to Ca 2+ mobilization from internal stores and a consecutive release of glutamate. Accumulating evidence supports the role of astrocytes in endocannabinoid mediated modulation of neural activity.
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