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Inflammatory and neurogenic pain: new molecules, new mechanisms
“I would have everie man write what he knowes and no more.”—MONTAIGNE
BRITISH JOURNAL OF ANAESTHESIA VOLUME 75, No. 2
AUGUST 1995 EDITORIAL
Inflammatory and neurogenic pain: new molecules, new mechanisms
Each of the reviews in this postgraduate issue of the journal shows how the classic picture of a single pain mechanism is being swept away in favour of a dynamic interlocking series of biological reactive mechanisms. Each of these mechanisms offers a deep understanding of reaction to tissue damage and also envisages better diagnosis and novel therapies. The classic teaching on pain had such enchanting simplicity that it was easy to learn and hard to forget. It therefore haunts us. Even now, when a new investigation reveals surprising unexpected mechanisms at work in part of the system, the investigators often assume that the rest of the classic story remains intact. Readers of this issue should therefore be warned to survey all the reviews because they will learn that little remains of the old story when the various new stories are put together. The classic model was a hard-wired, line-labelled, modalityspecific, single pathway which led from stimulus to sensation. Most research workers over the past hundred years understood their duty to be to label the axons and nerve cells which constituted this single relay and transmission system. It began in tissue with the fine myelinated and unmyelinated afferents which had such high thresholds that they responded only to noxious stimuli. They were cautiously labelled “nociceptors” by Sherrington because he realized that impulses in such fibres would not inevitably lead to pain unless the central nervous system accepted them and transmitted them to a pain-producing destination. In spite of this caution, the sensory nerve fibres and the cells on which they end are frequently labelled pain fibres and cells, thereby confusing the stimulus with the response. The nociceptors end preferentially on cells in the most dorsal laminae of the dorsal horn. Among these cells, there are a few which respond only to noxious stimuli, the nociceptive-specific cells. These naturally attracted special attention for those seeking “pain cells” in spite of the fact that their responses were too sluggish to correlate with aversive behaviour in behaving animals. The next leap in the classic pain pathway was to the thalamus by way of spinothalamic fibres which ran in the ventrolateral white matter of the spinal cord. This jump, based on the analgesia produced by a ventrolateral cordotomy, had to ignore the great majority of fibres cut by such a lesion which terminate in many brainstem structures other than the thalamus. It also had to fail to recognize the common chronic failure of cordotomy in which pain recurs. The selection of the thalamus and then the cortex as the site of the pure sensation of pain was
based on the untested Victorian assumption that therein lay the basis of all sensation. This key final target has persisted in medical school curricula in spite of the abysmal failure of surgical lesions in the forebrain from pulvinar to hypothalamus to produce persistent analgesia. The final myth sustained by classic teaching is that research would reveal the site of pure sensation to be located in thalamus and sensory cortex whose activity wouid be followed by the perception of the misery of the sensation by association areas of cortex. Let us start again and observe how the reviews in this issue re-examine the actual changes from periphery to cortex and shape a very different picture. The old picture of fixed property nociceptors implanted in damaged tissue passively detecting the chemistry of cell breakdown no longer holds. The huge power of modern molecular biology now shows an elaborate action and reaction of all cells, including the sensory nerve fibres in the region of damage. The tissue breakdown products have both direct and indirect effects on sensory afferents. White cells attracted into damaged tissue by leukotrienes carry out more than phagocytosis, since they secrete cytokines which have powerful local and systemic effects. Neurotrophins such as nerve growth factor are locally synthesized and play a part in pain production. The sympathetic nerves play a role in the inflammatory process beyond their release of noradrenaline and effect on blood flow. New receptors appear in tissue including novel alpha receptors and a type of bradykinin receptor and opiate receptors. The role of the unmyelinated sensory fibres themselves in inflammation as proposed by Sir Thomas Lewis is now fully established and identified as caused by peptides emitted from stimulated C-fibres. Most surprising, a group of C-fibres which appears to be completely silent in normal tissue is activated by ongoing inflammation and adds a novel component to the afferent barrage originating from damaged tissue. This combination of active cellular involvements forms a highly organized biological reaction which separately provokes vasodilatation, swelling, cell invasion and pain. The central nervous system is informed of the presence of tissue damage by the afferent fibres in two quite different ways. The obvious route is by way of nerve impulses produced in characteristic spatial and temporal patterns in the sensory fibres which have been changed by their contact with damaged and inflamed tissue. The second way is by the relatively slow transport of chemicals from tissue
124 along axons centrally to the dorsal root ganglion cells. These substances which include the neurotrophins change the metabolism of the dorsal root ganglion cell body and thereby the chemistry of the cytoplasm and cell membrane of the entire cell including its central terminal arborizations. In this way, the afferent nerve fibres, particularly the unmyelinated C-axons, are acting as the chemical pathologists of the body, literally tasting the chemical nature of the tissue in which they terminate. In response to changes in the nature of the transported chemicals, the entire chemistry and therefore physiology of the sensory cell changes. This has consequences not only in the peripheral tissue but, postsynaptically, in the central nervous system. The first central cells on which the afferents terminate are the antithesis of dedicated relay cells. They form integrated groups which compute by summation and differentiation. Particular input signals are received and merged in the context of other events in the periphery, and the past history and the setting of the nervous system, which is designed to select the most relevant activity to the biology of the entire organism. This inevitably implies that there are powerful inhibitory controls in the region and it was natural that pharmacologists and physiologists would search for the details of these inhibitory mechanisms from which useful analgesic therapy would emerge. It was not equally obvious that these cells would also be embedded in equally powerful facilitation mechanisms. The examples of the gross hyperexcitability states such as the deafferentation syndromes were attributed to a failure of the inhibitory mechanisms. However, it now appears that there are specifically excitatory mechanisms also present. They become particularly active following inputs of noxious origin and play a part in the widespread tenderness which reaches way beyond the area of injury. The chemistry of these mechanisms of exalted excitable states is now being discovered and offers a type of therapy which will prevent the prolonged hyperexcitabilities. These compounds are not analgesics in the sense that they produce pinprick analgesia since they act only on the prolonged aftermath of injury rather than on the initial signals. While there has been a huge and exciting increase in our understanding of the periphery and first central cells, the same cannot be said for deeper parts of the nervous system. As the review by Stamford shows, there is considerable new knowledge of the
British Journal of Anaesthesia way in which the brainstem exerts a descending control on the receptivity of the first central cells. What is still missing is an understanding of the biological circumstances in which these controls come into action. Their action may be crudely but usefully imitated by the use of new and old drugs but this does not explain the reason for their existence. It shows that the brain has a mechanism to control its own input but we do not know when, where and how this is brought into action in real-life. The reason for the obvious.paucity of our, detailed understanding of the deeper reaches of the central sensory mechanism is partly technical and partly philosophical. One conclusion is obvious from pathological lesions and from intentional neurosurgical lesions. Beyond massive destruction of the input, no discreet lesions ever produce a complete long-lasting analgesia. Therefore, the system we.seek to analyse must be a distributed one.But, and this is a very large but, up to now, we have had no experimental techniques by which we could analyse distributed systems. For the past hundred years, wonderful methods have been developed for the detailed analysis of the anatomy, physiology and chemistry of single cells and very limited groups of interacting cells. However, these limits may be being rapidly and fundamentally changed by the appearance of imaging techniques. Methods such as positron emission tomography, single photon emission computed tomography and functional magnetic resonance imaging for the first time allow us the possibility of a three-dimensional analysis of widespread activity in space and time. At this early stage, there is the expected conundrum by which attempts are made to explain the results of 21st century techniques in 19th century terms. Pain has been a particular target and the results reveal widespread activity in completely unexpected areas, coupled with lack of activity in the predicted old favourite targets. It is clear that the old model of a single dedicated localized pain centre is pure fantasy. The resolution of the problem will require some wide ranging new thinking derived from the results of these new techniques. We do not have that resolution but the next few years are going to be revolutionary. P. D. WALL Division of Physiology UMDS St Thomas’s Hospital Lambeth Palace Road London SE1 7EH
BRITISH JOURNAL OF ANAESTHESIA VOLUME 75, No. 2
AUGUST 1995 EDITORIAL
Inflammatory and neurogenic pain: new molecules, new mechanisms
Each of the reviews in this postgraduate issue of the journal shows how the classic picture of a single pain mechanism is being swept away in favour of a dynamic interlocking series of biological reactive mechanisms. Each of these mechanisms offers a deep understanding of reaction to tissue damage and also envisages better diagnosis and novel therapies. The classic teaching on pain had such enchanting simplicity that it was easy to learn and hard to forget. It therefore haunts us. Even now, when a new investigation reveals surprising unexpected mechanisms at work in part of the system, the investigators often assume that the rest of the classic story remains intact. Readers of this issue should therefore be warned to survey all the reviews because they will learn that little remains of the old story when the various new stories are put together. The classic model was a hard-wired, line-labelled, modalityspecific, single pathway which led from stimulus to sensation. Most research workers over the past hundred years understood their duty to be to label the axons and nerve cells which constituted this single relay and transmission system. It began in tissue with the fine myelinated and unmyelinated afferents which had such high thresholds that they responded only to noxious stimuli. They were cautiously labelled “nociceptors” by Sherrington because he realized that impulses in such fibres would not inevitably lead to pain unless the central nervous system accepted them and transmitted them to a pain-producing destination. In spite of this caution, the sensory nerve fibres and the cells on which they end are frequently labelled pain fibres and cells, thereby confusing the stimulus with the response. The nociceptors end preferentially on cells in the most dorsal laminae of the dorsal horn. Among these cells, there are a few which respond only to noxious stimuli, the nociceptive-specific cells. These naturally attracted special attention for those seeking “pain cells” in spite of the fact that their responses were too sluggish to correlate with aversive behaviour in behaving animals. The next leap in the classic pain pathway was to the thalamus by way of spinothalamic fibres which ran in the ventrolateral white matter of the spinal cord. This jump, based on the analgesia produced by a ventrolateral cordotomy, had to ignore the great majority of fibres cut by such a lesion which terminate in many brainstem structures other than the thalamus. It also had to fail to recognize the common chronic failure of cordotomy in which pain recurs. The selection of the thalamus and then the cortex as the site of the pure sensation of pain was
based on the untested Victorian assumption that therein lay the basis of all sensation. This key final target has persisted in medical school curricula in spite of the abysmal failure of surgical lesions in the forebrain from pulvinar to hypothalamus to produce persistent analgesia. The final myth sustained by classic teaching is that research would reveal the site of pure sensation to be located in thalamus and sensory cortex whose activity wouid be followed by the perception of the misery of the sensation by association areas of cortex. Let us start again and observe how the reviews in this issue re-examine the actual changes from periphery to cortex and shape a very different picture. The old picture of fixed property nociceptors implanted in damaged tissue passively detecting the chemistry of cell breakdown no longer holds. The huge power of modern molecular biology now shows an elaborate action and reaction of all cells, including the sensory nerve fibres in the region of damage. The tissue breakdown products have both direct and indirect effects on sensory afferents. White cells attracted into damaged tissue by leukotrienes carry out more than phagocytosis, since they secrete cytokines which have powerful local and systemic effects. Neurotrophins such as nerve growth factor are locally synthesized and play a part in pain production. The sympathetic nerves play a role in the inflammatory process beyond their release of noradrenaline and effect on blood flow. New receptors appear in tissue including novel alpha receptors and a type of bradykinin receptor and opiate receptors. The role of the unmyelinated sensory fibres themselves in inflammation as proposed by Sir Thomas Lewis is now fully established and identified as caused by peptides emitted from stimulated C-fibres. Most surprising, a group of C-fibres which appears to be completely silent in normal tissue is activated by ongoing inflammation and adds a novel component to the afferent barrage originating from damaged tissue. This combination of active cellular involvements forms a highly organized biological reaction which separately provokes vasodilatation, swelling, cell invasion and pain. The central nervous system is informed of the presence of tissue damage by the afferent fibres in two quite different ways. The obvious route is by way of nerve impulses produced in characteristic spatial and temporal patterns in the sensory fibres which have been changed by their contact with damaged and inflamed tissue. The second way is by the relatively slow transport of chemicals from tissue
124 along axons centrally to the dorsal root ganglion cells. These substances which include the neurotrophins change the metabolism of the dorsal root ganglion cell body and thereby the chemistry of the cytoplasm and cell membrane of the entire cell including its central terminal arborizations. In this way, the afferent nerve fibres, particularly the unmyelinated C-axons, are acting as the chemical pathologists of the body, literally tasting the chemical nature of the tissue in which they terminate. In response to changes in the nature of the transported chemicals, the entire chemistry and therefore physiology of the sensory cell changes. This has consequences not only in the peripheral tissue but, postsynaptically, in the central nervous system. The first central cells on which the afferents terminate are the antithesis of dedicated relay cells. They form integrated groups which compute by summation and differentiation. Particular input signals are received and merged in the context of other events in the periphery, and the past history and the setting of the nervous system, which is designed to select the most relevant activity to the biology of the entire organism. This inevitably implies that there are powerful inhibitory controls in the region and it was natural that pharmacologists and physiologists would search for the details of these inhibitory mechanisms from which useful analgesic therapy would emerge. It was not equally obvious that these cells would also be embedded in equally powerful facilitation mechanisms. The examples of the gross hyperexcitability states such as the deafferentation syndromes were attributed to a failure of the inhibitory mechanisms. However, it now appears that there are specifically excitatory mechanisms also present. They become particularly active following inputs of noxious origin and play a part in the widespread tenderness which reaches way beyond the area of injury. The chemistry of these mechanisms of exalted excitable states is now being discovered and offers a type of therapy which will prevent the prolonged hyperexcitabilities. These compounds are not analgesics in the sense that they produce pinprick analgesia since they act only on the prolonged aftermath of injury rather than on the initial signals. While there has been a huge and exciting increase in our understanding of the periphery and first central cells, the same cannot be said for deeper parts of the nervous system. As the review by Stamford shows, there is considerable new knowledge of the
British Journal of Anaesthesia way in which the brainstem exerts a descending control on the receptivity of the first central cells. What is still missing is an understanding of the biological circumstances in which these controls come into action. Their action may be crudely but usefully imitated by the use of new and old drugs but this does not explain the reason for their existence. It shows that the brain has a mechanism to control its own input but we do not know when, where and how this is brought into action in real-life. The reason for the obvious.paucity of our, detailed understanding of the deeper reaches of the central sensory mechanism is partly technical and partly philosophical. One conclusion is obvious from pathological lesions and from intentional neurosurgical lesions. Beyond massive destruction of the input, no discreet lesions ever produce a complete long-lasting analgesia. Therefore, the system we.seek to analyse must be a distributed one.But, and this is a very large but, up to now, we have had no experimental techniques by which we could analyse distributed systems. For the past hundred years, wonderful methods have been developed for the detailed analysis of the anatomy, physiology and chemistry of single cells and very limited groups of interacting cells. However, these limits may be being rapidly and fundamentally changed by the appearance of imaging techniques. Methods such as positron emission tomography, single photon emission computed tomography and functional magnetic resonance imaging for the first time allow us the possibility of a three-dimensional analysis of widespread activity in space and time. At this early stage, there is the expected conundrum by which attempts are made to explain the results of 21st century techniques in 19th century terms. Pain has been a particular target and the results reveal widespread activity in completely unexpected areas, coupled with lack of activity in the predicted old favourite targets. It is clear that the old model of a single dedicated localized pain centre is pure fantasy. The resolution of the problem will require some wide ranging new thinking derived from the results of these new techniques. We do not have that resolution but the next few years are going to be revolutionary. P. D. WALL Division of Physiology UMDS St Thomas’s Hospital Lambeth Palace Road London SE1 7EH