We've heard from Professor Mary on the endo-cannabinoid system. We now know that the system includes cannabinoid receptors CB1 and CB2, two endogenously produced cannabinoids, and the two main enzymes which metabolized endo-cannabinoids. With this in mind, we now try to understand the physiological effect of cannabis on pain systems in the brain. It is a known fact that there is an extensive expression of CB1 receptors in several areas in the brain. These include, the cortex, the hippocampus known for its role in relation to memory and deep brain structures such as, limbic system associated with emotions. CB1 receptors are also found in areas clearly associated with pain processing in the brainstem and in the spinal cord. So, it's fairly clear that activation of these receptors by THC can interfere with brain circuits in the central nervous system. If you'll recall our discussion about the transmission in the synapse, CB2 receptors are located presynaptically, and their activation inhibits the release of neural transmitters. Numerous animals studies have shown a direct relationship between pain and cannabinoids. In animal models of nerve injuries, we see an increase expression of CB1 receptors, suggesting that cannabinoids are effective for neuropathic pain. So, it's not surprising that injection of cannabinoids into the spinal fluid reduces pain behavior in animals. In contrast, pharmacological blocade of CB1 receptors in the central nervous system produces hyperalgesia or hypersensitivity to pain in animal models. But this is not where the story ends. Studies from recent years show that apart from neurons, immune and others support cells in the central nervous system called microglial cells and astrocytes, are also heavily involved in pain processing. Evidence show that CB2 receptors, which are typically found outside of the central nervous systems are also expressed on astrocytes and microglia. Thus, suggesting that cannabis can have an additional central effect on pain processing through CB2 receptor mediation. A few words on tolerance to these effects. Data from both animal and human studies suggest that tolerance to the analgesic effective THC in the brain can develop. If such tolerance indeed occurs, dosage may need to be increased over time, a factor of which can potentially influence the development of dependence and even addiction in some users. This tolerance appears to be related primarily to CB1 receptors. In fact, tolerance, dependence and addiction to cannabis share a common biological CB1-mediated mechanisms. However, tolerance has also been shown for CB2 receptor induced analgesia in rat brains. So, analgesic tolerance may be less selective than previously thought, and involve both CB1 and CB2 brain receptors. At the same time, tolerance to adverse effects such as sedation and cognitive impairments can certainly be an advantage. In a control study, acute neurocognitive impairment in response to 0.5 milligram per kilogram of THC, was significantly higher in occasional cannabis users than in heavy users. In parallel, chronic cannabis smokers show a higher rate of down regulation of CB1 receptors in cortical brain areas than occasion users. This indicates that heavy use of cannabis results in the development of tolerance.
