There have been a lot of very heated arguments for and against the use of cannabis for medical reasons. Pharmacologists and neurobiologists have been busy studying away to find out how cannabis actually goes about producing its therapeutic effects in order to find alternatives to administering cannabis so that we can avoid the nasty side effects associated with the drug. THC is the active ingredient found in cannabis, it is part of the super family of compounds known as the cannabinoid.Credit: http://www.postmodernmoron.com/2011/02/20/cannabinoids-and-stem-cells/
Cannabinoid compounds bind to CB1 and CB2 receptors. CB1 receptors are located within central and peripheral neurones while CB2 receptors are expressed mainly in immune cells. The binding of cannabinoids to their receptor produces a number of therapeutic effects in the brain and body, these include a reduction in the perception of pain, reduction in levels of inflammation, prevention of epileptic seizure and increasing appetite in patients suffering from Wasting Syndrome. However, the administration of drugs that contain cannabinoid compound and cannabis like medicine induce side effects such as sedation, impaired cognitive abilities and physcotic behaviour due to the activation of the wide CB1 receptors in the brain. This therefore, minimises the benefits experienced when exogenous cannabinoids are used for therapeutic use.Credit: http://www.nature.com/nrc/journal/v3/n10/box/nrc1188_BX1.html
Since the discovery of the cannabinoid system, we have realised that our bodies have the capability of producing their very own cannabinoid compounds such as Anandamide and 2AG , these products are known as the endocannabinoids. They are able to bind to the cannabinoid receptors and activate them the same way as ingesting cannabis-based medicine. Studies have revealed these compounds are present throughout the body but they are found at higher levels where pain or inflammation is involved. It is thought the presence of these compounds at such levels have the ability to bring analgesic effects. This has led scientists to believe that targeting the levels of endocannabinoids instead of their receptor sites can be used for therapeutic reasons. Increasing the levels of endocannabinoids at key sites of pain and inflammation could a way of treamenting patients who suffer from neuropathic diseases associated with pain.Credit: http://www.emc.maricopa.edu/faculty/farabee/BIOBK/biobookenzym.html
The biological effects of the endocannabinoids are often short lived because they are rapidly metabolised by enzymes or transported into cells. This, therefore, reduces the levels of analgesia the endocannabinoids can provide. The amount and the duration of action of the endocannabinoids can be increased by blocking enzymes which degrade these compounds. Fatty acid amide hydrolase is the main enzyme responsible for the metabolism of Anandamine and can also metabolise 2AG. The absence of the Fatty acid amide hydrolase gene in mice causes a 15 fold increase in the amount of anandamide present compared to normal mice who have the gene. Inhibiting the action of Fatty acid amide hydrolase enzymes with drugs such as URB597 increases the levels of anandamide and 2AG while producing prolonged effects of analgesia. Monoacylglycerol lipase is the main enzyme responsible for the breakdown of 2AG. There have been difficulties in finding inhibotrs for this enzyme because the agents often are not selective for this particular enzyme, this has lead to only few studies being conducted and the effects still remain unclear until a selective inhibtor of Monoacylglycerol lipase has been found.
The inhibition of Fatty acid amide hydrolase and Monoacylglycerol lipase enzymes should potentially increase the levels of endocannabinoid. However, the endocannabinoid are able to undergoing metabolism via other routes. The cyclooxygenase(COX2) is the most heavily studied route where the endocannabinoids undergo metabolism following the inhibition of Fatty acid amide hydrolase and Monoacylglycerol lipase. It has also been suggested that the presence of COX2 in the spinal chord is heavily involved in the mediation of pain, this makes sense if these enzyme are responsible for breaking down the very compounds causing a reduction in the level of pain. Therefore, blocking COX2 along with Fatty acid amide hydrolase and Monoacylglycerol lipase should increase the levels of endocannabinoids.
Victoria chapman and her team from Nottingham University wanted to compare the effects of inhibiting COX2 and Fatty acid amide hydrolase enzymes on the levels of endocannabinoids. A behavioural study was conducted by setting up a model of inflammatory pain in rats by injecting carrageenin into the hindpaw. This caused their paw to swell up due to the infiltration of white blood cells into the infected site. Nimesulide was used as a COX2 inhibitor because is relatively selective for the COX2 enzyme and is not able to inhibt the actions of the Fatty acid amide hydrolase enzyme and this was important because they wanted to observe the route of metabolism the endocannabinoids took when Fatty acid amide hydrolase was blocked.
The animals were placed in a chamber where they had to sit on their back feet, the weight distribution between the inflamed and the non inflamed feet were calculated to determine the level of inflammation in their paw. Over time the animals placed less weight on their inflamed paw than their non inflamed paw. The animals were then injected with a saline containing Nimesulide and URB597, this caused the animals to have equal weight distribution between their inflamed and non inflamed paws. The results also showed the levels of endocannabinoids in the carrageenin treated hindpaw which did not have Nimesulide was significantly lower than the saline treated hind paw which contained both Nemesulide and URB597. The lower levels of endocannabinoids in the non Nemesulide treated carrageenin hindpaw was a result of endocannabinoids being metabolised by the COX2 enzymes when only the Fatty acid amide hydrolase enzymes were inhibited. When both the Fatty acid amide hydrolase and COX2 enzymes were inhibited there were higher levels of endocannabinoids compared to when only the Fatty acid amide hydrolase enzymes was inhibited.Credit: http://www.tokeofthetown.com/2010/06/oregon_reclassifies_marijuana_as_medicine.php
The duration of action of the endocannabinoids can be increased by reducing the amount of compounds transferred into cells. This can be achieved by blocking the proteins such as TRP1 which are present in the cell membranes and are responsible for transferring the endocannbinoid compounds from the external environment into the cells cytoplasm.