Cannabis may be better known for its mind altering effects in 1 in 20 adults globally each year, but substances found in this drug, or compounds with a similar structure can also be used for the purpose of treating pain.
For such beneficial effects to be provided there must first be an interaction of these compounds, known as cannabinoids, with a certain class of receptors within our central nervous system and peripheral tissue. However the interaction can sometimes produce harmful effects as well. The inhibitory CB1 cannabinoid receptors were the first to be discovered and were found to produce desirable analgesic effects. Unfortunately there were simultaneous side effects which compromised the analgesia seen with the cannabinoids. As a result these CB1 receptors could not be exploited for the purpose of treating pain.
To overcome the problem of separating unwanted side effects from pain relief, there is now an exciting new approach being considered by several research groups and pharmaceutical companies to target the other CB2 cannabinoid receptor. Originally these receptors were only thought to be associated with the organs that have an important immune function such as the spleen. As such nobody suspected that it would have any role in pain processing. However Phillip Malan and his team from the U.S.A recently conducted some research to suggest otherwise. He demonstrated that CB2 receptor agonists, ligands or drugs which bind to these receptors altering their activity, may potentially cause an analgesic effect and suppress neuropathic pain. Now unlike nociceptive pain, such as a burn or bruise, which causes pain signals to be sent to the brain by nerves, neuropathic pain is caused by injury to the peripheral or central nervous system itself. A key symptom is pain caused from just the slightest touch also known as allodynia. Unfortunately the main problem with neuropathic pain is that it is very difficult to manage clinically with conventional analgesia. Therefore the alternative CB2 receptors sparked great interest among those working within the pain field.
However an even more surprising discovery was that such receptors may actually adapt according to the state of the individual, so that they are only produced when a person starts to develop neuropathic pain. Victoria Chapman and her team at Nottingham University first identified that a particular drug targeting the CB2 receptor, known as JWH133 managed to reduce pain in the spinal cord of rats. Work published by Zhang and colleagues around the same time showed that the mRNA of these CB2 receptors could only be found in neuropathic and not naive rats. This potential plasticity of the CB2 receptors was tested and confirmed by Chapman. Rats that suffered from allodynia showed significant inhibition of responses from spinal neurones following treatment with the JWH133 drug. On the other hand control rats treated with the same drug showed no inhibition of responses from their spinal neurones. These experiments suggest that there may be some kind of novel functional role of CB2 receptors in neuropathic rats.
Although these results are encouraging it could not be the end of the story as pain is not solely mediated by the spinal cord.
“In fact the spinal cord makes quite a small contribution, in my opinion, compared to the overall contribution of the brain, both in terms of ascending pain pathways and descending pain pathways,” says Chapman.
An intriguing study revealed that these CB2 receptors can also be found in the brains of patients suffering from Alzheimer’s disease. Based on this finding Chapman’s team went on to consider the potential novel functions of these CB2 receptors within the brains of neuropathic animals. What they discovered was that if JWH133 was administered into the amygdala, an area within the brain, there was significant inhibition of allodynia. The effects were more prolonged when higher doses were administered. This positive finding means that we can look forward to a greater chance of success at treating even more pain related conditions in future.
However while such studies provide new evidence for a role of CB2 receptors in neuropathic animals and suggest that they can alter allodynia, it is not fully understood exactly how these CB2 receptors work to bring about such pain relief. Nevertheless there have been a number of interesting suggestions to explain this phenomenon. One attractive theory is that perhaps because these receptors are associated with our immune cells, they actually alter the immune response within the spinal cord during neuropathic pain. Another equally attractive option is that these receptors which are located on peripheral nerves could cause a decrease in neurotransmitter release in neuropathic animals, so there is a decreased level of excitability reducing the level of pain in such individuals. While both are plausible suggestions, neither can be confirmed as yet. Only further research will reveal the true mechanism used by CB2 receptors to relieve pain.
Although these findings have the potential to reap great benefits, there is still disagreement about how effective this approach will be at achieving neuropathic pain relief. Perhaps future research on CB2 receptors could be collaborated with work based on understanding how the natural endocannabinoids found in our bodies work, as they too could be targeted for the purposes of providing pain relief. Nevertheless despite the controversies, current work has opened up new doors of hope to all those suffering from neuropathic pain and could be the key stepping stone needed to ultimately find the cure for this debilitating condition.