Pain is an intensely personal experience, frequently unpredictable in its strength and duration. In his extraordinary book In the Land of Pain, Alphonse Daudet, the 19th-century French novelist and playwright who suffered the agony of tertiary syphilis 'tabes dorsalis', describes an "armour... a hoop of steel cruelly crushing my back. Hot coals, stabs of pain as sharp as needles." Pain like this can take over your life. It is no longer simply a warning, a demand for attention or a trigger for escape, recovery and healing but has become a body state. "Very strange the fear that pain inspires nowadays - or rather this pain of mine. It is bearable and yet I cannot bear it. It's sheer dread, and my resort to anaesthetics is like a cry for help."

Ludwig Wittgenstein was fascinated with the link between the existence of pain and pain language and behaviour. Pain behaviour, like groaning, can point out a painful place, he argued, but the subject of pain is the person who gives it expression. "If someone has a pain in his hand, then the hand does not say so and one does not comfort the hand, but the sufferer; one looks into his face."

The concept of pain as an essentially conscious human (or human-like) experience does not preclude it also being a sensation. To the neurobiologist, the basis of human experience and behaviour lies in the neuronal circuitry of the brain. Most of us argue that there is no need to draw upon a 'ghost in the machine' - to borrow philosopher Gilbert Ryle's evocative metaphor - to explain the complexities of human thought and experience: the answer lies in the integrated activity of the cells and tissues of which we are composed, if only we could understand them. While our ability to explain human emotions in terms of neuronal activity lies outside our current understanding of brain function, the neuronal mechanisms that underlie the sensation of pain present a fascinating and solvable problem.

Thus the aim of the neurobiologist is to work out the cellular mechanisms that underlie the processing of pain stimuli in the brain. What changes are triggered by pain-inducing stimuli - in the activity of genes or the production of proteins in cells, in the behaviour of individual or groups of neurons, or in whole areas of the brain. Understanding these biochemical and neurobiological responses opens up the possibility of developing agents that will interfere with these changes, and prevent the sensation we experience and describe as pain.

Understanding pain
The last 25 years has seen the most fantastic growth in neurobiology and in our knowledge of the basic pathways responsible for nociception - the sensory detection of painful stimuli and their signalling to the brain. We understand a lot about the peripheral nerve fibres that respond to tissue damage and something of their ability to convert mechanical, chemical or thermal stimuli into electrical signals sent to neurons in the spinal cord. We have insight into the complex neuronal circuitry in the spinal cord and brainstem. We can describe the chemical transmission that allows the message to jump across the synapses in the brain. The advent of brain imaging has shown us the areas of the human brain that are active as we experience pain. Even the analgesic actions of morphine - the active ingredient of opium, used as a painkiller for 6000 years - can be explained at a mechanistic level.

Such knowledge alone, however, would have remained confined to the textbooks if it had not been recognized that the circuitry of the brain is not constant but malleable or 'plastic'. Thus the strength of connections between neurons is not fixed, but varies in response to different signals.

The recognition that plasticity is fundamental to pain can be largely credited to Patrick Wall (1925-2001), who worked for much of his career at University College London. A neurophysiologist of consummate skill, Wall was one of the first biologists to record the activity of sensory neurons in the brain and spinal cord in response to painful stimulation. He was also immensely well read, with an insight into the psychology and philosophy of pain rare in a biologist.

With his colleague Ronald Melzack, a psychologist at McGill University in Canada, Wall developed a theory of how pain is processed by the brain that broke away from the traditional views. He saw that despite the advances of modern technology, many scientists worked within a simple Cartesian model of sensation where designated pain pathways operated like a rope attached to a bell in a church tower, causing a 'ringing' in the brain when pulled. Even Descartes in his later work had rejected this model as too simple to explain complex phenomena such as phantom limb pain, but modern scientists are notoriously resistant to lessons of history or philosophy.

Throughout his life, Wall argued that sensory signals triggered by injury do not simply get passed on at central synapses, like a baton being passed from runner to runner, but are actively modified on their way to the brain. Pain is often likened to an early warning system, a flashing light that something is amiss. But it is much more sophisticated than that. Most importantly, the activity triggered by the injury can itself alter the system's capacity to respond. Typically, it becomes sensitized to further stimuli, a form of memory. This sensitization may happen at the site of the injury in peripheral nerve endings but, crucially, it can also occur within the brain itself. Because the central processing area is affected, signals from other parts of the body, including those unrelated to the original injury, may also be processed differently. Such a model explains such phenomena as referred pain (pain appearing to originate in an undamaged part of the body), allodynia (pain due to a stimulus that does not normally provoke pain) and phantom limb pain, as well as the prolonged pain some people endure after an original injury has healed.

Wall also highlighted the importance of inhibition as well as activation within the brain. In addition to the pathways leading from areas of the body to the spinal cord and up to the brain, powerful inhibitory or dampening influences emanate from regions deep in the brain, send messages down the spinal cord, and shut off sensory inputs where they enter the spinal cord and brainstem. Without them, the abundance of sensory inputs available at any one time would lead to a catastrophic overload and trigger epileptic fits. In some circumstances, these mechanisms can block out pain all together, even in the face of the most horrendous injury. Nociception is thus a balance between excitation and inhibition, and unfortunately in some circumstances an imbalance between the two may have the opposite effect, leading to chronic pain.

Wall's legacy

The insight of Wall and his colleagues has set the agenda for today's research endeavour. The mechanisms by which the presence of pain alters the very nervous system that is processing it are complex indeed, and much of current pain research is aimed at discovering exactly what is going on. Huge numbers of neuroscientists are contributing to a rapidly burgeoning knowledge base, tackling particular discrete elements of the overall picture. They also differ markedly in their approach to pain. There are those who believe that conquering pain will lie in the isolation of single genes coding for key proteins. Others feel that only by studying activity in neuronal circuits in the whole animal, complex though this is, will pain processing be understood and controlled. Still others are convinced that important clues lie in the development of pain processing in infants and children, in whom the nervous system is still maturing.

Daudet was doubtless right when he said that there is "no general theory about pain. Each patient discovers his own, the nature of the pain varies, like a singer's voice, according to the acoustics of the hall". Perhaps pain is too complex, too subjective for us ever to say we have cracked it. But as a neurobiologist, I believe that a mechanistic approach to the sensory aspects of pain can and will give control to the patient and lead to relief of suffering.

See also

'Pain' exhibition microsite includes a collection of reviews on pain research.

External links

Professor Maria Fitzgerald (Professor of Developmental Neurobiology) at University College London: Research interests