Are you in pain? It’s a standard question to ask someone who looks uncomfortable. Note the intriguing use of language. You don’t ask someone, are you in pneumonia, or in flu? However, when pain occurs it can take over and occupy your life – you are in pain – a captive, trapped by your body’s own alarm system.
"The relief of pain remains a major challenge in modern medicine," says University College London’s Professor of Neuropharmacology, Anthony Dickenson. However, pain has proved to be remarkably difficult to tackle.
Pain is a very personal experience, partly because there is no truly objective way of measuring it. However, in the last decade scientists have gained a more thorough understanding of the mechanisms that trigger pain and the neural pathways that transmit pain signals to the brain, raising hopes for more effective treatment strategies in the future.
The pain pathway
Exposure to heat or damage to tissues stimulates C-fibers, a set of fine nerve fibers that run from the skin and other tissues to the spinal cord. Within the spinal cord, they form connections with other fibers in a structure called the dorsal horn. These fibers then carry the pain signals on to the brain. This route, from tissue through the spinal cord to the brain is called the pain pathway, and there are numerous ways of potentially blocking or disrupting it.
Blocking pain in the periphery
One possibility is preventing the C-fibers from being stimulated. All nerves conduct messages by allowing minute pores to open and close in their membranes. These pores regulate the flow of sodium ions in and out of the nerve fiber, allowing signals to pass along. Local anesthetics block these sodium channels, and if their action is blocked, the nerve can no longer transmit signals, including pain. However, local anesthetics have drawbacks. If they escape into the blood circulation, the anesthetics can block sodium channels in other areas, including the heart and brain.
C-fibers are triggered by excessive heat. "The issue is, why don’t C-fibers respond until the temperature is up to 42 degrees centigrade – an extreme temperature – why don’t they respond before?" asks Dickenson. The answer, he explains, is that C-fibers contain a specialized form of sodium channel that only opens at temperatures that are likely to cause damage. Working at University College London, Dr John Wood has thoroughly analyzed this channel. It has been isolated and genetically engineered into bacteria so that large quantities can be produced and studied. The race is now on to find a chemical that can block its action while leaving all other sodium channels unaffected. "How many companies are chasing this idea is anyone’s guess, but you can guarantee that they are," says Dickenson with a smile.
An interesting note: These channels also respond to capsacin, the hot component of chili peppers, which explains why a curry feels ‘hot’ rather than feeling like you are chewing glass.
Another approach to preventing C-fiber stimulation is to block the production of prostaglandin, a chemical released from a tissue as part of its inflammatory response to damage. One of its actions is to stimulate C-fibers. A group of drugs called non-steroidal painkillers blocks the action of the prostaglandin-producing cyclooxygenase enzymes COX1 and COX2. However, a major problem with these compounds is that they are indiscriminate in their action, and block the enzymes in locations like the blood vessels and stomach wall, where prostaglandins play an important role in maintaining healthy tissue. In blocking chronic pain, you can end up causing stomach ulcers.
However, there is renewed hope that this approach may work. It now appears that while COX1 is present in almost all tissues, COX2 is present in particularly high concentrations in damaged tissues. There are now some drugs that are capable of specifically blocking COX2.
Dickenson points out that COX2 is also constantly present in the brain, although no one is quite sure what function it has there. Its presence, though, could explain why non-steroidal painkillers like paracetamol, which can block COX2, are pretty good at inhibiting pain in situations like fever, even though they do nothing to reduce inflammation.
Dickenson comments that a big issue with new generations of painkillers will be their high price relative to the cost of drugs like aspirin and paracetamol.
Dealing with pain that results directly from injured nerves is also a major clinical problem. Most of the drugs that are showing signs of tackling this neuropathic pain were originally designed as anticonvulsants, antidepressants, and antiepileptics. Among the newcomers to the field, gabapentin appears to present the most hope. Its mode of action is unclear, but it probably operates by blocking calcium channels in the neurons, and clinical trials show that it can be quite effective. The sodium channel blockers discussed above could also be of great importance in treating neuropathic pain.
Blocking pain in the spinal cord
Yet another approach to blocking pain is to allow the C-fibers to become stimulated, but block the transmission of their signal within the dorsal horn of the spinal cord. The major neurotransmitter involved in this process is glutamate, and there are many pharmaceutical companies focussing on the task of blocking the N-methyl-D-aspartate (NMDA) receptor that glutamate binds to. The problem is that these drugs currently have many adverse side effects, such as sedation, so at the moment they are given as a last resort. However, there appear to be many sub-types of the receptor, raising the hope that it might be possible to block the NMDA receptors that mediate pain without inducing side effects.
Within the spinal cord, a peptide known as substance P plays an important role in transmitting pain signals from one neuron to another. Speaking at the Society for Neuroscience held in Miami in October 1999, Dr Ronald Wiley of Vanderbilt University and Veteran Affairs Medical Center, Nashville, explained that when substance P becomes attached to its receptor on the surface of a neuron, the receptor-substance P conjugate is drawn inside the cell. This has given a number of researchers the idea of attaching a toxin to substance P and injecting it alongside the pain pathway. The theory is that the toxin will be drawn only into fibers associated with transmitting pain and will selectively kill them. Work in laboratory animals indicates that this approach has a potentially powerful effect. Dickenson, however, is skeptical about any approach aimed at destroying elements of the nervous system in order to reduce pain. "The idea seems great," he says, "but prior to this modern wave of intervention in pain, surgeons used to treat chronic pain by cutting nerve tracts in the spinal cord - the pain went away for a bit and then returned with a vengeance. I’m not sure that these toxins will fare any better."
Blocking pain in the brain
Drugs acting in the periphery are useful because they don’t need to get into the central nervous system and so don’t cause side effects associated with central nervous system function. However, as we have seen there are multiple peripheral mechanisms that trigger pain, and you can only block one at a time. Drugs like the opioid morphine, which acts within the brain, can block all pain. "Opioid-like drugs have been around for at least three millennia and are arguably the most valuable drugs in medicine," claims Dickenson.
The trouble with opioids is their side effects of addiction, euphoria, and a reduced ability to think clearly. Opioids bind to receptors in the membranes of neurons and prevent the neurons from firing. Morphine works on the mu-receptor, but delta-receptors, kappa-receptors, and, more recently, opioid receptor-like 1 receptors (ORL1) have been discovered. The hope is that a drug will be developed that can bind to the correct ratio of the different types of opioid receptors so that it kills pain without inducing the adverse side effects of morphine. "At the moment it looks as though concentrating on the delta-receptors could provide the best way forward," says Dickenson.
The neurotransmitter serotonin (also known as 5-HT) is involved in some cases of migraine, and drugs that block its ability to bind to nerves are capable of blocking migraine-associated pain. This role of serotonin also explains why some people suffer from migraines after consuming red wine or chocolate, as both of these contain high quantities of chemicals that the body can turn into serotonin. It also explains why migraines are one of the potential side effects of specific serotonin re-uptake inhibitors (such as Prozac) used as antidepressants, as they allow the concentration of serotonin in the brain to increase.
Finally, cannabis may prove useful in the fight against pain. This compound stimulates two different receptors named cannabis 1 and cannabis 2, although it appears that cannabis 1 is the predominant receptor in the brain. Dickenson is keen to see the results of a number of Canadian trials that are testing to see if the drug operates predominantly through its mood altering properties or whether it really is a potent analgesic.
Conclusion
Pain plays a useful role in that it alerts us to damage to our bodies. Problems arise when the siren sounds too loud and for too long. The next few years should see new drugs that promise a more intelligent and directed approach to releasing hundreds of thousands of people from the captivity of being in pain.
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