In this article, Anthony Dickenson and Rie Suzuki (University College London) look at the mechanisms involved in pain.
Why we feel pain
In this article, Anthony Dickenson and Rie Suzuki (University College London) look at the mechanisms involved in pain.
When you sense that any part of your body is in harms way or has been damaged in some way you experience pain. Look at what happens when you touch a hot surface – your hand recoils automatically. And if you cut your finger while chopping veggies, you instantly drop the knife and clutch your finger. Your body knows automatically when to move away from a painful stimulus.
Why is this?
People, like many living things, have developed systems that provide a warning of potential or actual damage to their bodies so they can move away from the painful stimulus. Some of these systems work by telling you where the pain is and how bad it is, while others activate muscles to enable you to move away from the painful stimulus. Then there are yet more systems that are responsible for the emotional aspects of pain – when you feel anxiety, fear or anger as result of pain.
Over the last few years, our knowledge of the mechanisms of pain and analgesia has improved, but still we don’t fully understand them, particularly in the case of pain that remains for long periods of time (chronic pain). In this situation, the survival or warning action of pain has an unclear function.
In the same way, neuropathic pain, which is generated as result of nerve injury, should predictably lead to numbness only, but patients frequently have pain as well. This is probably because we have systems that can enhance, amplify and prolong pain as a further warning mechanism, but with chronic neuropathic pain these go wrong or outlast their usefulness in the short term.
The nature of the pain from nerve injury is unlike everyday pains. The pain can be spontaneous – being there without a stimulus – or can be triggered by stimuli.
Spontaneous pain can be either constant or intermittent (episodic). Most patients with neuropathic pain describe having both – constant “burning” pain plus intermittent “shooting” or “electric shock-like” pain.
Pain triggered by stimuli often includes allodynia, where sensations that do not usually cause pain, like cooling, gentle touch, movement or pressure, now evoke pain. In other situations, stimuli that are normally painful can be perceived to be even more painful, and this is known as hyperalgesia. People with neuropathic pain also often report abnormal sensations like crawling, numbness, itching, and tingling.
The symptoms of neuropathic pain are similar despite the many causes of nerve injury. Apart from direct trauma or damage, neuropathic pain occurs in 20% of patients with diabetes, a similar number of patients with shingles and can also occur after HIV infection and surgery. It is also one of the most difficult painful symptoms to control in many cancer patients.
Neuropathic pain is produced by changes in the nervous system as a result of the nerve injury. These changes make the nervous system hypersensitive, and can occur in both the peripheral nervous system (all nerves outside the brain and spinal cord, including those in the torso, and arms and legs) and in the central nervous system (nerves in the brain and spinal cord).
In order to understand how nerve damage causes changes in the nervous system and neuropathic pain, we must first take a look at the pain processes that occur in the periphery.
The first stage in the transmission of acute pain (caused perhaps by grabbing something hot) involves the activation of specialized sensory receptors called nociceptors. Nociceptors are present on a set of peripheral nerves, called C-fibres, and are found in your skin, muscles and other parts of your body.
Nociceptors can sense and respond to a variety of painful stimuli, including strong pressure or a pinch (mechanical stimuli), hot and cold (thermal stimuli) and chemical stimuli (like chilli peppers). This is because a nociceptor is not a single entity. Instead, it is made up of a number of receptors and channels that sense and respond to painful stimuli.
In the case of chilli peppers, we have known for a long time that the hot ingredient in them, capsaicin, evokes a sensation of burning pain. We now know that this is because it activates a particular receptor that is our heat sensor.
We have a huge range of channels and receptors that allow peripheral nerves to respond to many stimuli and, importantly, send messages (electrical signals) that we are in pain from the periphery through the spinal cord to the brain (to the central nervous system), where they reach our consciousness.
What happens when tissues are damaged?
When you actually damage a part of your body (or tissues) in some way, say for example sprain an ankle, nociceptors not only get a message to the brain that you are in pain but also play a part in stopping you from causing further damage to the injured part of your body.
The damaged tissues release a cocktail of chemicals, including a group called prostaglandins, which cause the injured area to become inflamed (red and swollen), and the nociceptors in that area to become particularly sensitive to other stimuli. These chemicals do not normally activate nociceptors directly but instead work to reduce the threshold required to activate C-fibres so that they now respond to lower intensity stimuli.
This is why you might feel pain when you apply even light pressure on an inflamed finger, or you feel excruciating pain when you get into a hot bath after being sunburnt. By feeling more pain in the injured area, you can take action to prevent damaging it further, like not putting weight on a sprained ankle.
The well-known painkillers called non-steroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, relieve pain by blocking the formation of the prostaglandins and thereby reduce the inflammation and sensitivity of the injured area.
The enzyme responsible for the formation of the prostaglandins is cyclo-oxygenase (COX), of which there are two forms – COX-1 and COX-2. The main action of the NSAIDs is to block COX-1, but because this form of the enzyme is present in other parts of the body, blocking COX-1 can cause the stomach problems and other side effects associated with the NSAIDs.
The second form – COX-2 – is different in that it is present only in inflamed areas following tissue damage. There are now newer painkillers available, called COX-2 inhibitors, that block only the COX-2 form of the enzyme. These are just as good as NSAIDs at reducing pain, but lack the potential stomach problems of the older medicines.
As well as prostaglandins, other chemicals including bradykinin and serotonin (also called 5-hydroxtriptamine or 5HT, and well known for its action in the pain associated with migraine and headaches) accumulate in damaged tissue, playing a part in the sensitization and the activation of C-fibres during inflammation.
Pain caused by inflammation or tissue damage can be produced by surgical procedures, trauma, cancer and other conditions like arthritis.
What happens when nerves are damaged?
When it is a nerve that is damaged people experience neuropathic pain. This pain is often long lasting (chronic) and includes both negative symptoms (sensory loss and numbness) and the positive symptoms of allodynia, hyperalgesia and ongoing pain that is unlike pain experienced when other sensory systems are damaged (crawling and tingling).
The negative symptoms make sense, given that a nerve has been damaged. The positive symptoms, however, are harder to explain, and strongly suggest changes within the nervous system that are excessive attempts to compensate for the sensory loss caused by the nerve injury.
Neuropathic pain is thought to begin in the periphery, within the nerve itself. Unlike acute pain or pain caused by tissue damage, the first events of neuropathic pain are independent of peripheral nociceptor activation.
When a nerve is damaged, a number of changes can be produced in the nerves, in terms of activity, properties and transmitter (chemical) content. Damaged nerves generate ongoing pain impulses in the absence of stimulation because of the accumulation and clustering of certain types of channel (called sodium channels) around areas of nerve damage. There is also evidence that the receptors that sense and respond to mechanical stimuli (strong pressure or a pinch) become highly sensitive to stimuli. This aberrant activity can then start to spread rapidly to parts of the central nervous system.
As well as the changes within the damaged nerve, injured nerves may become oversensitive to chemicals released from other nerves, leading to their activation. This can cause spontaneous pain and prime the spinal cord to have exaggerated responses to stimuli, which themselves have greater effects due to increased sensitivity of the peripheral nerves.
A lot of the information about the changes in the periphery following nerve damage has become known relatively recently. This has helped us understand why medicines that block sodium channels, like the epilepsy treatment carbamazepine, are helpful in controlling neuropathic pain.
Reaching our consciousness
Although tissue and nerve damage activate peripheral nerve fibres in different ways, both cause electrical signals to run into the spinal cord, at which point chemical messengers take over, passing the message onwards from nerve to nerve until the final pain messages reach our consciousness.
However, it is not as straightforward as it sounds. Once the pain signals reach the spinal cord, various mechanisms operate to further amplify and prolong the stimulus.
As we discussed at the beginning of this article, pain signals whether generated from tissue damage or nerve injury begin their journey to our consciousness (the brain) in peripheral parts of our body, like the torso, arms and legs.
Networks of special nerves (C-fibres) in the periphery convey pain signals, as electrical signals, to the spinal cord. When pain signals reach the spinal cord, the central nervous system (nerves in the spinal cord and brain) takes over from its peripheral counterpart, and various mechanisms operate to ensure we become aware of the magnitude of the pain and experience the emotional aspects of pain, like anxiety and fear.
We have two systems that are of prime importance in pain within the central nervous system – the excitatory system and the inhibitory system. The excitatory system enhances pain signals to ensure they remain strong for long enough for the journey onwards to the brain. The inhibitory system controls pain signals to reduce pain. The excitatory system predominates in most conditions, which is why an absence of pain after trauma is a rare event confined to short periods of time on the battlefield or in a sports event.
The excitatory system
Nerves carrying pain signals from the periphery such as the skin, converge at an area of the spinal cord called the dorsal horn. Here the pain signals switch from being electrical in nature to chemical. The chemical messengers that take over are called transmitters. There are several different types of transmitter, but most of the nerves arriving in the dorsal horn of the spinal cord contain a transmitter called glutamate.
The transmitters, which are released by calcium channels in the spinal cord, activate (or ‘excite’) nerve cells in the dorsal horn so that they can pass the pain signals upwards to the next nerve in the spinal cord and the next and so on until the signal finally reaches the brain. This process involves thousands and thousands of nerves scattered throughout the brain.
Analgesics like gabapentin and pregabalin, which are used to treat neuropathic pain, are thought to work by interacting with calcium channels to reduce the amount of transmitter released into the spinal cord in response to pain signals. This results in there being less activation of the nerves that send pain signals to the brain, and in this way the pain is dampened.
Once pain signals reach the brain a number of things can happen. Some of the nerves that terminate in the brain are designed to allow us to locate the pain and describe its intensity. Others make contact with areas in the brain that cause fear, anxiety and the stressful responses that pain generates. En route the nerves can also reach parts of the brain that control sleep, appetite and our attention to the outside world.
So pain can cause sleep problems, make us anxious and fearful, and by activating the part of the brain to do with attention, can take over our responses to the outside world, meaning social interactions and work can suffer.
Furthermore, these emotional and other responses to pain connect back to the nerves in the spinal cord and amplify the pain signal further so that the pain increases. Coping, distraction and living a normal life as possible can reduce this amplification.
So a network of spinal and brain circuits can change spinal sensitivity to pain signals arriving from the periphery and regulation of this by pathways that lead away from the brain can link the level of spinal cord sensitivity to the behavioural and environmental context.
Other pain enhancing pathways
These pathways are not the only ones in the central nervous system that can make pain signals increase. When the special nerves in the periphery that convey pain signals (C-fibres) are stimulated greatly again and again, as happens when we experience persistent pain, this causes an amplification and prolongation of the response to the pain signal by the nerves in the dorsal horn. This means the pain gets worse and worse even though the painful stimulus stays the same. This phenomenon is called ‘wind-up’.
We can demonstrate wind-up in people. One example is if you put a painful heat stimulus on the hand of someone with neuropathic pain 10 times, they will feel more and more pain with each application even though the intensity of the heat remains the same throughout the test. This is wind-up, and it means pain felt after the tenth heat stimulus seems much more painful than that experienced after the first application. Because of wind-up, a relatively minor peripheral pain stimulus can cause severe pain that often lasts longer than the stimulus.
Wind-up occurs when a receptor on nerves in the dorsal horn called an N-methyl-D-aspartate, or NMDA, receptor becomes activated by the chemical transmitter glutamate in response to pain signals. When NMDA receptors are activated a higher number of nerves in the dorsal horn become activated per painful stimulus.
Repetitive episodes of wind-up can cause a phenomenon called long-term potentiation (LTP), which is similar to memory. When LTP occurs the spinal cord becomes hypersensitive to incoming pain signals. It ‘remembers’ a peripheral pain stimulus as being more intense than it is. As a result, greater pain messages are sent to the brain and incoming pain messages are translated into allodynia, where sensations that do not usually cause pain, like cooling, gentle touch, movement or pressure, now evoke pain.
NMDA receptor activation plays a predominant role in the sensitisation process involved in many persistent pain states, like inflammation and neuropathic pain.
There are a number of drugs that can block the activation of the NMDA receptor, including the licensed medication ketamine, which is potent but often not used because it has unacceptable side-effects.
The inhibitory system
Just as there are parts of the central nervous system that can amplify pain signals, there are also certain parts that can inhibit or muffle incoming pain signals to reduce the amount of pain we feel.
The amount of pain we feel can be reduced by the production of endorphins, which are morphine-like substances that occur naturally in the body. Stress, excitement and vigorous exercise are some of the things that can stimulate the production of endorphins. This is why an athlete may not notice the pain of a fairly serious injury until after the sports event has finished.
The pain relieving opioid medications, like morphine, work by mimicking the action of the naturally occurring endorphins. Opioids work in the brain and dorsal horn of the spinal cord. We know more about how they work in the spinal cord. Here they reduce the amount of chemical transmitter released from the nerves carrying pain signals from the periphery (C-fibres) so that the nerves in the dorsal horn are less excited (activated) by incoming painful messages. Opioids also block nerves in the spinal cord from passing on the pain signal to the next nerve and the next and so on, so that information fails to reach the brain, or our consciousness.
Opioids like morphine can provide excellent pain relief in patients where the pain is acute but can be less effective if the pain syndrome is neuropathic in origin, as in the case of phantom limb pain, where pain signals seem to arise from amputated limbs. That said, it is now accepted that at least some patients do obtain pain relief with opioids following nerve injury.
One other important inhibitory system is in the brain that can alter activity in the spinal cord. The transmitters are noradrenaline and serotonin in these pathways. If their levels increase, pain reduces. Examples of drugs that increase their levels are antidepressants. Thus, they can also be used to control pain, even though a patient may not be depressed.
On the whole we have a good understanding of the basic mechanisms of pain transmission and analgesia, and know that hyperexcitability (when our body is particuarly sensitive to pain) can be set up both peripherally and centrally. We are also beginning to understand the complex links between pain and emotions.
Most of the events that cause pain are invisible, being hidden deep in our peripheral nerves, spinal cord and brain. Although invisible we know they are real! The drugs used to treat pain have logical mechanisms and we understand the targets. Due to the links between pain and emotions, not giving in to the pain, learning to cope and distraction have positive impacts. Many experts feel that movement and exercise are also beneficial in helping to control pain.
Although we know more about pain than many other diseases and disorders of the nervous system, there are still many areas where our understanding of pain remains inadequate. For example, there may be a some degree of genetic basis to individual differences in levels of pain, the transition from acute to chronic pain, differences in susceptibility to neuropathic pain after nerve damage and in analgesic effectiveness, but this is yet to be determined.
In order for pain to be better controlled, the knowledge we have of the mechanisms of pain needs to be translated into therapy. There is a great deal of work currently going on in this field.