Cannabinoids is a general term used to describe compounds that are structurally similar to that of the compounds found inside the cannabis plant (Lambert & Fowler, 2005). Throughout history the cannabis plant has been utilised by man for a wide range of different purposes: from the stalk of the cannabis plant being used to produce the fibres to make hemp to the cannabis plant being used for its medicinal properties to treat and ease pain in many conditions including gout, menstrual pain and arthritis (Hoskings & Zajicek, 2008). However, by far the most commonly known and most widespread use of cannabis in recent times is as an illegal recreational drug. Its popularity is so high because of the psychoactive properties of one of the substances present in the cannabis plant, delta-9-tetrahydrocannabinol (Î”9-THC); Î”9-THC causes the feeling of relaxation and happiness (Manzanares et al., 2006). In recent decades there has been a resurgence in interest over the pain management properties of cannabinoids and this has resulted in more research into the use of cannabinoids in the treatment of chronic pain. To date there have been many enquires and trials, several of which have produced promising results, supporting the use of cannabinoids in pain management. This essay aims to study cannabinoids and their action within the body and also their effectiveness in treating chronic pain.
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Cannabinoids and Cannabinoid Receptors
Compounds that are described as cannabinoids can be further sub-divided into three distinct groups based on where they are located. (Shown below in table 1).
Table 1: Sub-groups of Cannabinoids
Sub-group of Cannabinoids
In the Cannabis plant, similar in structure to Î”9-THC
Synthetic (man-made) cannabinoids, these are the most diverse class of cannabinoids, can have classical or non-classical structures.
In the nervous systems of animals. (Can also be found in the immune system)
Table 1: Original Table: Showing the different sub-groups of cannabinoids, where they come from and also an example of each. Information in the table obtained from (Pacher et al., 2006).
Cannabinoid pharmacology and our understanding of cannabinoids only first properly began in the early 1960s, although man had been using the cannabis plant, for many different purposes for hundreds of year previous (Hosking & Zajicek, 2008). This was a result of advances in chemistry techniques for isolating and studying a compound's structure. With these advances in technology the first cannabinoid, cannabinol (CBN) was discovered in 1963 and since then many more compound's structures have been isolated and identified (Pacher et al., 2006).
Following on from this research, that was aimed at cannabinoid discovery and identification, a new focus emerged in the field of pharmacodynamics of cannabinoids (how they behave in the body). This new area of research resulted in the discovery of two cannabinoid receptors (CBR), CB1R and CB2R. These receptors are G protein coupled receptors (GPCR) and possess seven transmembrane domains which are connected to a heterotrimeric G-protein made up of three non-identical sub-units (Î±, Î², and Î³) (Graham et al., 2009). Figure 1 below shows the structure of a GPCR, such as the cannabinoid receptors CB1R and CB2R.
Figure 1: G-Protein Coupled Receptor Structure
7 transmembrane domains
Figure 1: GPCR Structure e.g. CB1R and CB2R
Taken from http://cae2k.com/db-photos-0/gpcr.html
and edited to highlight important areas of its structure
CB1 receptors are found to be expressed mainly in the brain and central nervous system, and in actual fact CB1 receptors have been found to be the most common GPCR in the CNS (Begg et al., 2005). However CB1 receptors are also located in other organs of the body including the kidneys, lungs and liver. CB2 receptors have been found to be abundant in the immune system and hematopoietic systems (Munro et al., 1993), and recent studies have indicated they are also present in brain (Pacher et al., 2006).
Pain Pathways and Cannabinoid Receptors
The emotion of pain is extremely complex, involving several signaling pathways and mechanisms. The pain pathway begins with the stimulation of primary afferent sensory neurons called nociceptors. These nociceptors transmit information about the stimuli to the dorsal root ganglia (DRG), which is located just outside the spinal cord and then on to the dorsal horn, which is located within the spinal cord. From here the dorsal horn exchanges information with the brain to add the emotional feeling of pain, this process is complex and not fully understood (Schmidtko et al., 2009).
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There is strong evidence to suggest that cannabinoid receptors (CB1 and CB2) are not only expressed in some of the areas involved in this pain pathway, but also that the cannabinoid receptors are involved in the signaling mechanisms. This suggests that cannabinoid receptors could be targeted by drugs to treat and manage pain. Figure 2, shown below provides a diagram of the pain processing pathway that is described above and also highlights the fact that cannabinoid receptors are present within it.
Figure 2: Nociceptive Pain Processing Pathway
Figure 2: Diagram of nociceptive pain processing pathway in which cannabinoid receptors are involved. Diagram taken from (Hosking & Zajicek, 2008).
Cannabinoids and their Therapeutic Potential in Chronic Pain
Over the last decade there has been a lot of emphasis has been placed upon research into the potential use of cannabinoids in treating pain caused by many different conditions, such as multiple sclerosis and Huntington's disease. These studies have been carried out using mainly animal models and there is muchevidence supporting the use of cannabinoids for such purposes. However, some studies have not produced such convincing results and have highlighted potential problems with cannabinoid treatment.
Multiple sclerosis (MS) is a neurodegenerative disease cause by the demyelination of the myelin sheath surrounding the nerve axons in the brain and central nervous system. This results in various symptoms which include, muscle weakening and severe pain (Sospedra & Martin, 2005). In 1989, a group studied the effects of intravenously injecting the cannabinoid Î”9-THC into a rat model of MS. Their results proved very interesting with the presence of inflammation in the CNS being dramatically reduced and the neurological processes of the body being significantly improved. In addition to this, the survival rates of the rats that were administered with Î”9-THC were a lot higher than the control rats (Lyman et al., 1989). In 1994, this experiment was repeated by Wirguin et al., however this time the rats were orally administered the cannabinoid Î”8-THC. Î”8-THC is a more stable and also less psychotropic cannabinoid compared to Î”9-THC, which is ideal as it would represent a potentially safer option for prescribing as a drug for humans. The Î”8-THC administered rats also showed significant improvement in inflammation of the CNS, improved neurological efficiency and also survival rates (Wirguim et al., 1994).
Both of theses separate studies provided promising results, indicating that cannabinoids may be useful in the treatment of chronic pain which is associated with the symptoms of MS. Similar results were also obtained in other animal models (mice models) of multiple sclerosis (Baker et al., 2000). These studies lead to the effects of cannabinoids on human MS patients being studied. One such experiment monitored the therapeutic benefits of using Î”9-THC to treat the painful symptoms of MS over a 12 month period. The end results were very positive and showed that Î”9-THC treatment improved several of the symptoms of the disease, including muscle pain and muscle spasticity without experiencing any side effects; this was demonstrated by the patients being scored over a period of time on the Ashworth scale (Zajicek et al., 2005).
Huntington's Disease (HD) is a genetic neurodegenerative disease that leads to the sufferer experiencing difficulties with motor movement of muscle, for example hyperkinesia (involuntary muscle spasms) and dementia. Currently the therapy options available to Huntington's disease patients are very limited (Melone et al., 2005), this prompted recent studies looking into cannabinoids as a potential treatment method for HD. It has been established through studies that one of the early causes of HD is a reduction in CB1 receptors in the basal ganlia region of the brain. This therefore decreases the levels of signaling in the basal ganlia which leads to the subsequent loss of nerves and the onset of the characteristic symptoms of the disease (Page et al., 2000). Scientists believe that the use of cannabinoid agonists may hold therapeutic benefit in HD patients because of the previously discovered protective properties that cannabinoids have on nerves. Experiments have been carried out treating rat and mice models of HD with cannabinoid agonists to determine if this theory is correct. The results show that the CB1 receptor agonist, CP55,940 does decrease hyperkinesia in the HD animal models in comparison to the control experiments.
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However, when these experiments were repeated for studying the effects in humans with Huntington's disease, using the cannabinoids nabilone and cannabidiol there was no significant visible reduction in hyperkinesia and in some cases the patient's hyperkinesia increased (Muller-Vahl et al., 1999). Although the authors of theses studies do acknowledge that the poor results maybe due to issues with the dosing of the drugs administered to the patients. In order to clarify if this is the case this issue should be addressed and the experiment repeated.
Cancer pain, more specifically the pain cancer patients suffer, is another area that cannabinoid research has targeted. One study wanted to study the effects of orally administering a single dose of benzopyranoperidine (similar compound to Î”9-THC) in treating cancer pain and compare its effects to that of a single dose of a currently used analgesics, in this case codeine. The results concluded that benzopyranoperidine's analgesic effects were no more effective than orally administered codeine (Jochimsen et al., 1978). Similar experiments were also carried out comparing Î”9-THC with codeine; they concluded that 10mg of Î”9-THC had the same analgesic effects as 60mg of codeine. Even when they increased the dose of Î”9-THC to 20mg it was still only as effective as120mg of codeine and, with the higher dose, unwanted side-effects also appeared, such as drowsiness and depression of the central nervous system (Noyes et al., 1975). Therefore these studies suggest that cannabinoids should not be used as a one-off treatment of pain, as they are no more effective than currently available analgesics like codeine. In addition to this there are also more adverse side effects to take into consideration with cannabinoids.
In 2001, a systematic review by Tramèr et al. studied cannabinoids effects in the treatment of sickness and nausea caused by chemotherapy. The results showed that the cannabinoids had antiemetic properties (prevented sickness and nausea) as the majority of the chemotherapy patients administered with cannabinoids did not feel nauseas or sick compared to the control chemotherapy patients. However, the studies did again highlight the possible issue of unwanted side-effects that is associated with cannabinoids (Tramèr et al., 2001).
In conclusion, the cannabis plant has been utilized by man for centuries in many different ways including medicinal purposes and more recently recreational drugs. Since the early 1960 there has been a lot of scientific interest in the cannabis plant and the discovery of compounds found within the plant, which are referred to as cannabinoids. Cannabinoid receptors have also been discovered in the human body, these receptors are expressed in place that are know to be involved in the pain signaling pathways. This resulted in research being carried out into the effectiveness of cannabinoids in the management of chronic pain; the results obtained have been somewhat mixed. Research has shown that cannabinoid treatment in patients suffering from multiple sclerosis significantly reduced chronic inflammatory pain of the CNS. In Huntington's disease patients there were both positive and negative results for cannabinoid treatment and it is agreed that more research is required before making definite conclusion. Experiments have also been carried out comparing the analgesic effects of the one off use of cannabinoids to currently used pain-killers (e.g. codeine); these experiments concluded that cannabinoids were no more effective and also cause more unwanted side effects.
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