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Pain Research New Clues for Drug Design
PAIN RESEARCH New Clues for Drug Design
The philosopher Rene Descartes proposed a pain mechanism whose action was enviably simple: when filaments of nerve are broken or pulled, a person experiences pain. Since Descartes' time, science has found that the circuitry underlying pain is astonishingly complex. Yet even the elaborate picture now revealed is not complete. Progress in the understanding of pain has depended on work in a number of scientific fields. Pharmacology, for example, has come to center stage since researchers found that nerve impulses travel by chemical means. The more that is learned about pain, the broader the scientific net that must be cast to discover the detailed mechanisms of cause, and to design successful therapies for the various kinds of pain.
Concepts Evolve Like many early scientific theories, Descartes' ideas about pain were profoundly revised in the course of later research. He had proposed a simple, direct pathway from physical injury to the pain experiellce. The first feature of the scheme to fail was the idea that one kind of pathway alone signals pain. In the late 1800s, physiologists mapped the spinothalamic (today the neospinothalamic) path along the spinal cord. They believed at first that in mapping this pathwayfrom the crossed afferent fibers of the spinothalamic tract, to the ventral nucleus of the thalamus, and from there to the somatosensory cortex-they had identified the entire pain system. Their work led physicians to treat
24
Descartes, in his 17th century "Treatise of Man," described his concept of the pain pathway, suggesting that if a noxious stimulus (A) damages the nerves, they send a pain ~essage by ~ straightforward, simple path (C) to the brain. By the 19th century, researc~ers r~alzzed. that t~lS concept was far too simple to explain the various types of sensory perceptIOn-mcludmg pam.
chronic pain by cordotomy and similar surgical procedures. Interrupting the spinothalamic pathway in this manner, it was thought, would prevent pain signals from reaching higher levels of the nervous system, where the signals are perceived. Results observed in subsequent years, however, suggested that the pain pathway in fact had not been found. Cordotomy sometimes relieved chronic pain, but pain often returned, and almost as often, the recurrent pain was more severe than the original pain.1/2 It was difficult to
reconcile these findings with the idea that the spinothalamic tract was the only messenger of pain. In the middle of this century, the new Nauta stain confirmed the pathway first marked, but it also revealed several others, including a multi synaptic pathway that ascends through the reticular formation. Researchers named this newly traced pathway the . pale 0 spinothalamic, and believed that it, together with the first-known neospinothalamic path, was the likely anatomy of the pain system. American Pharmacy Vol. NS22, No.3, March 19821136
Today, even this elaborate circuit is considered only a partial picture. Physiologists now think that at lE~ast six afferent pathways are involved in signalling pain. Such an arrangement greatly complicates the understanding of pain syndromes and the design of effective treatments.
Further Complexities Throughout the history of pain research, physiologists have proposed that some peripheral nerve receptors respond only to painful stimuli while others respond only to heat or cold or touch. This stimulus-specificity of receptors is one' possible explanation of how different kinds of environmental events cause different kinds of sensation. The idea of receptor specificity got its modern interpretation in the electrophysiological studies of Nobel laureates Gasser and Erlanger. In the 1920s they discovered that the most peripheral afferent nerve fibers could be classified by their conduction velocities. Nerve conduction velocities differ because myelinated fibers carry impulses faster than do unmyelinated fibers, and large fibers faster than fine ones. Other researchers found that the small fibers-both myelinated (Adelta) and unmyelinated (C)-respond most to noxious (normally painful) stimuli, and the large Abeta fibers respond most to touch. Receptor specificity is well established today as a general physiological fact. Not only have peripheral fibers been found that are sensitive only to touch, for example, but nearly a dozen distinct types of these so-called low-threshold mechanoreceptors have been identified .because of their special responses to vibration, movement and pressure. 3 Researchers have also found several types of pain fibers: some Adelta fiberf respond only to strong mechanical stimuli; other A-deltas respond to noxious heat as well; the C fibers respond to a variety of noxious stimuli-chemical, thermal and mechanical. While receptor specificity may explain some sensations of pain, it cannot explain some of the symptoms of chronic pain. In post-herAmerican Pharmacy Vol. NS22, No.3, March 19821137
A stalked cell is one of several kinds of cells located in the substantia gelatinosa (layer II of the spinal cord). The thicker branches toward the. bottom are dendrites which receive sensory information. Toward the top is a thinner branched axon which transmits information to higher levels of the eNS. Researchers draw pictures of these cells by hand from microscopic views of the cells to enable further study of pain pathways.
petic and trigeminal neuralgias, for example, .it is light touch, not noxious stimulation, that triggers paroxysms of pain. Similarly, phantom limb pain lacks a usual stimulus, and may persist years after injured tissue has healed and when pain receptors should not be active. Another aspect of pain that is not explained by receptor specifictty is the influence of emotion on response to pain. Beecher's classic study of men who were wounded on the field during World War II provided dramatic examples of emotion's effect on pain. Elated at escaping from battle alive, many severely wounded soldiers claimed to feel no pain at all and refused analgesic medications. 2 On a lesser scale, the severity of pain depends on its significance and on social and emotional features of the injured person's situation. These phenomena suggest that the action of specific pain receptors can only partly explain the range of pain experience. The activation of
so-called pain receptors by injury is not always accompanied by pain, nor, as chronic pain conditions demonstrate, is it necessary to activate these receptors for pain to be felt.
Contemporary Theory . Recently a gate control theory was proposed to account for these and other anomalies. 2 In outline, the theory is that certain nerve cells in the spinal cord behave like gates. The gates open when activity in small-diameter p~i mary pain-signalling fibers excites these cells, and shut when these cells are inhibited by activity in large primary afferents that ordinarily sig-· nal touch. Gate cells also can b~ inhibited by some of the many descending pathways that terminate in the spinal cord. The gate cells compute a kind of average of these various inputs and send the processed message -along with other messages of this type-on . to higher levels of
the brain where the final message is received. Gate control theory is consistent with two of the most successful ideas of modern neurophysiology: • That inhibition is as common as excitation in the normal working of the nervous system; • That sensory systems are not straight-through, passive information shunts from the world to consciousness, but rather are active processors of information, passing it through successive filters, abstracting only the most important features. This second idea explains why so much attention is given to the spinal cord in pain research: in the spinal cord are the first way stations-the first synaptic 'c onnections-at which incoming information is processed. 'Equally important, gate control theory explains psychological and physiological facts that were unexplained by traditional theory. It explains why some pain syndromes, like the post-herpetic and trigeminal neuralgias, are associated with damage to large primary afferents. The theory is that if activity in large fibers is pathologically interrupted, the fibers cannot inhibit , gate cells and, from the gate cells' point of view, signals from small pain fibers appear enhanced. Since gate cells weigh the relative activity of the two kinds of fiber, in these syndromes the cells send on a message of pain. Gate control theory might explain the common experience of being able to attenuate pain by rubbing the painful area. Exciting large touch-sensitive fibers in this way closes the gate. The theory may also provide a potential account of the more exotic results of acupuncture. Effective acupuncture points are those where large fibers predominate. 4 The stimulation of these points by needling might enhance large fiber activity and drown out the activity of small fibers that would otherwise signal pain. The gate is a mechanism that can account for the sometimes profound effects of social and emotional factors on pain: inhibitory pathways that descend from higher levels of 26
the CNS can shut the gate more or less completely depending on how a person evaluates the circumstances of his or her injury. The more recent theory has been a tremendous impulse for research and for designing pain therapies. Transcutaneous electrical stimulation (TNS) is just one suggested ,by the gate theory. About half the patients who suffer chronic pain from peripheral nerve injury respond to TNS, a therapy which seems to have no adverse effects. In its outline form, and in its emphasis on information processing and descending control, the gate theory still directs pain , research. But the results of research it has led to indicate that the theory's details must be changed.
Interdisciplinary Approach In the 1950s, Rexed mapped the complex, highly organized cytoarchitecture of the spinal cord, revealing new features of the pain circuit. He found that the spinal cord consisted of distinct layers, or laminae, each distinguished by its own kinds of nerve cells and nerve cell connections. He identified them with the Roman numerals I-X. Researchers have proposed that gate cells might be found in the superficiallayers of the dorsal horn, in Rexed's lamina II, a region corresponding roughly to that known for more than a century as the substantia gelatinosa, owing to its gelatinous appearance when observed under a light microscope. Re,c ent electrophysiological, immunocytochemical and electron microscopic research indicate, however, that this region is much more complicated than was thought when the gate theory was first proposed. These findings make it increasingly evident that understanding the circuit's numerous parts and functions will require an interdisciplinary approach. ' The neurobiology and anesthesiology branch of the National Institute of Dental Research (NIDR) at the National Institutes of Health is one laboratory that empasizes such an interdisciplinary approach in its research on pain. Its methods include clinical, psychophysical, be-
havioral, electrophysiological, and immunohistochemical techniques. Fine anatomical studies have demonstrated unexpected complexities in the region proposed as the gate. Neuroanatomists at NIDR have found that the substantia gelatinosa itself contains not one, but most likely at least five kinds of local neurons. The best characterized so far are stalked and islet cells. 5 On the basis of electron microscope and other studies of their fine features and synaptic connections, stalked cells are thought to have an excitatory role in relaying pain information, doubling back their message to lamina I from which the message travels to higher levels of the CNS. Similar studies suggest that islet , cells are inhibitory. Through the I elaborate connections they make with primary fibers, stalked cells, I and perhaps other local neurons, they are believed to playa complex, I mediating role in the processing of pain information. Dr. Stephen Gobel at NIDR believes that the substantia gelatinosa's structure is complex and regular, consisting of two distinct layers. Whatever gating occurs in the substantia gelatinosa, then, occurs in a more complicated way than researchers first thought. Identification of the substantia gelatinosa's circuit diagram is not yet complete; neither is identification of the area's functions nor their significance in terms of human experience. Here, interdisciplinary research will be required to find the answers. I
Classifying Pain Psychophysical stUdies at NIDR classify the different types of pain as they are felt, so that eventually these types can be correlated with various physiologic states of- the pain system. Correlation of psychophysical and physiological data has already suggested an explanation for some kinds of pain response. An unpleasantly hot stimulus provokes both first" and "second" pains-a sharp and well-localized pain followed by a burning diffuse sensation that follows about a second later. The latencies of first and II
American Pharmacy Vol. NS22, No.3, March 1982/138
Corticosteroids have been used in the treatment of alcoholic hepatitis with the rationale that the disease is characterized by an inflammatory process and that immunological factors may playa significant role in'its pathogenesis. The results of the clinical trials to date have been variable as to the effectiveness of corticosteroids for all degrees of severity of alcoholic hepatitis. It appears that they are most effective if given in high doses to biopsy-proven alcoholic hepatitis patients who have severe clinical symptoms.14
Alcoholic Cirrhosis The most severe form of alcoholic liver diseaseJ alcoholic cirrhosis (Laennec's cirrhosis), is irreversible. It is essentially the end-stage scar lesion of alcoholic liver disease, characterized by diffuse, nodular fibrosis surrounding areas of normal or regenerated hepatic tissue. This results in alteration of the normal hepatic architecture and a decrease in the ability of the liver to perform its metabolic functions. The scarring of alcoholic cirrhosis is generally believed to be a reaction to the hepatocyte necrosis and inflammation of alcoholic hepatitis. The immunologic response that is thought to be significant in the pathogenesis of alcoholic hepatitis may also cause progression to cirrhosis. 15 This mechanism may be responsible for those alcoholic hepatitis patients who, despite abstinence from alcohol, develop cirrhosis. Yet, additional pathways must also exist in the pathogenesis of alcoholic cirrhosis because the disease has been demonstrated to develop without any apparent intermediate alcoholic hepatitis stage. 16 One possible explanation is that collagen production is stimulated in the hepatocyte as a result of the metabolism of alcohol. It is hypothesized that because of this stimulated collagen production, accumulation occurs within the hepatocyte with eventual fibrosis ensuing. Whatever the pathogenesis of alcoholic cirrhosis, the major clinical manifestations and sequelae of the disease are a consequence of the American Pharmacy Vol. NS22, No. 4, April 19821195
eventual impaired liver functions ' erally thought to be irreversible. and of the disrupted architecture Therefore, the goals of therapy are (see box above). not to reverse the pathologic process, but to prevent the progression One major function of the normal liver that is altered in' the cirrhotic . of the disease and manage the disease complications. patient is its ability to metabolize potentially harmful substances. The two most frequent causes of Thus, the metabolism of exogenous death in patients with cirrhosis are substances, such as drugs or ingastrointestinal bleeding (from esophageal varices) and complete gested toxins, as well as endoliver failure (hepatic coma). genous substances, such as estroIt has been shown that although gens, aldosterone, bilirubin, and the disease is irreversible once pabiogenic amines, is impaired. thologic changes have occurred, the The resulting excesses of these five-year survival rate is significantsubstances are responsible for the ly increased in those patients who following clinical manifestations: abstain from alcohol and undergo feminization characteristics, sodium aggressive supportive management and water retention which conof these disease complications. 17 0 tributes to peripheral edema and ascites formation, jaundice, and hepatic coma. References Additionally, the liver is normally 1. H. G, Zimmerman, "Hepatotoxicity: Adverse Effects responsible for the production of of Drugs and Other Chemicals on the Liver," Appleton-Century Crofts, New York, 1978. certain coagulation factors and vas2. C. S. · Lieber and E. Rubin, American Journal of Medicine, 44, 200 (1968). cular proteins. Decreases in their 3. C. S. Lieber, Clinics in Gastroenterology, 10, 315 (1981). prod uction are characterized by a 4. H . D. Lipsitz, et al., Gastroenterology, 81, 594 (1981). 5. J. T. Galambos, Gastroenterology, 63, 1026 (1972). hemorrhagic tendency in the pa6. K. C. Gaines and M. F. Sorrell, Medical Clinics of tient, and contribute to ascites and North America, 63, 495 (1979). 7. K. J. Isselbacher, Nw England Journal of Medicine, 296, peripheral edema. 612 (1977). 8. O . Johnson, Scandinavian Journal of Gastroenterology, 2, The major sequela of a disrupted 207 (1974). hepatic architecture is portal venous 9. C. S. Lieber and R. Schmid , Journal of Clinical Investigation, 40, 394 (1961). hypertension which develops sec10. E. Baraona, et al., Journal of Clinical Investigation, 60, ondary to obstructed blood flow 546 (1977). 11. P. B. Beeson, W. McDermott and J. B. Wyngaarden, within the liver. This obstruction reeds. , " Textbook of Medicine, 15th Edition," W. B. sults not only in the clinical manSaunders Co., Philadelphia, 1979. 12. S. M. Sabesin, et al. , Gastroenterology, 74, 276 (1978). ifestations of a swollen portal ve13. C. L. Mendenhall, et al. , Clinics in Gastroenterology, 10, nous system (esophageal varices 417 (1981). W. C. Maddrey, et al., Gastroenterology, 75, 193 (1978). and splenomegaly), but also in de- _ 14. 15. S. Kakumu and C. M. Leevy, Gastroenterology, 72, 594 (1977). creased deliverance of potential tox16. H. Popper and C. S. Lieber, American Journal of Pathins to the liver for metabolism. ology, 98, 695 (1980). 17. M. M. Figler and J. G. Rankin, eds., " Alcohol and The fibrotic changes that characthe Liver," Plenum Press, New York, 1976. terize alcoholic cirrhosis are gen-
27
The significance of this finding is that, even at the level of the spinal cord, it is not just the physical value of a stimulus that determines whether nerve cells will fire, but also what the stimulus means. Information is apparently filtered very early in the sensory process depending on what it has come to indicate about other environmental events. Descending inhibitory pathways probably function as a screen so the animal can focus on just those events most important for survival. This highly adaptive mechanism may be clarified in other studies at NIDR. Researchers there are using electrophysiological methods to study pathways that descend to pain cells in the spinal cord. One major pathway projects from the nucleus raphe magnus in the midbrain through the dorsal horn. Researchers have found that cells in this area (dorsal horn) of the spinal cord that respond to noxious stimuli can be shut down by stimulating cells in the nucleus raphe magnus. This finding indicates that the nucleus's natural function is to inhibit ' pain messages; perhaps it provides a mechanism through which emotional and motivational influences act.
Neuropharmacology Another major area of research at NIDR concentrates on the rapidly growing field of neuropharmacology and the actions of neurotransmitters and neuromodulators in pain pathways. Immunocytochemical and autoradiographic studies of the dorsal horn have revealed an abundance of different possible transmitting substances in its superficial layers. Enkephalin, cholecystokinin, Substance P, and somatostatin (found throughout the CNS) are among those localized in the hypothetical gate region. Pain researchers know that enkephalin depresses pain-signaling cells, possibly by the same mechanism that morphine does: its action on pain cells-like that of morphine -is antagonized by naloxone. Somatostatin is another endogenous substance that inhibits pain, but its effect is not counteracted by nalox-
28
one; thus, knowing somatostatin's mode of action could provide the basis for developing non-narcotic analgesic agents. Similarly, study of excitatory substances in the pain system, like Substance P, may lead to the design of new pharmacological agents for pain treatments. If Substance P is a principal chemical messenger of pain, knowing its manner of action will enable researchers to design drugs to interrupt that action at some point, thus alleviating pain. Understanding the physiological action of neurotransmitters and neuromodulators has required the development of elegant techniques, several of which are used at NIDR.
Research on the physiology and neurochemistry of pain should lead to drugs that are more effective . ..
For example, in micro iontophoresis, minute amounts of putative transmitter substances are placed near individual cells by specially designed microscopic equipment. The effect of the substance on a cell is measured and compared to that cell' s response to noxious stimuli. If the substance affects the cell in the same way that natural stimulati<;m does, it is considered as the chemical messenger for that link of the pain circuit. New in vitro studies also provide an opportunity to observe the effects of different substances on nerve cells in ionically controlled microenvironments . For example, normal synaptic action requires the presence of calcium. A substance may be applied to a cell in a calciumfree environment to determine whether the substance acts directly or by presynaptic mediation. One other puzzle arose from the gate theory as it was originally proposed: a few large fibers respond to noxious stimuli and quite a number of small fibers respond to touch, contrary to the general rule. This paradox might be resolved by neuropharmacological research, if pain
fibers could be classified by their neurotransmitters rather than by their size or electrical properties. This may be found to be true, but as has happened so many times before, investigators have revealed a new twist in an already tangled story-many fibers contain more than one neurotransmitter.
New Drugs It may seem that basic research on pain only poses more and more new puzzles; but it also has resolved a few. The new nonsteroidal anti-inflammatory agents, for example, were devised specifically as a result of basic research. Investigators knew that prostaglandins were released at the periphery by damaged tissue and that they hypersensitized pain fibers. So, molecular engineers set out to design agents to interfere with prostaglandin release . The drugs that resulted include . zomepirac sodium, ibuprofen arid sodium naproxin. These drugs have proved to be highly effective analgesic agents for a wide variety of pain conditions, including dysmenorrhea and the chronic pain of osteoarthritis and cancer. Zomepirac sodium, in particular, is as powerful as usual doses of codeine and other narcotics. Yet these agents are not addictive, and patients don't develop tolerance to them even after extensive use. No doubt, through further basic research on the physiology and neurochemistry of pain, new pharmacological agents can be designed for currently intractable pain. Such research should eventually lead to drugs that are even more effective, specific and benign. -Ann Covalt American Pharmacy correspondent
References 1. H. C. Voris and W. W. Whisler (eds.), "Trea tment of Pain," Charles Thomas, Springfield, IL, 1975.
2. R. Melzack, "The Puzzle of Pain," Basic Books, Inc., New York, 1973. 3. j . Bonica (ed .), "Pain, Discomfo rt and Humanitarian Care, " Elsevier North Holland, Inc., Amsterdam, 1980. 4. Lu Guowei el al., Chinese Medical Journal, 94, 255 (1981).
5. S. Gobel el al., The Journal of Comparalive Neurology, 194, 781 (1980).
6. R. Melzack, Pain 1, 277 (1975). 7. R. Dubner, D. S. Hoffman and R. L Hayes, Journal of Neurophysiology (in press).
American Pharmacy Vol. NS22, No.3, March 1982il~
i
The philosopher Rene Descartes proposed a pain mechanism whose action was enviably simple: when filaments of nerve are broken or pulled, a person experiences pain. Since Descartes' time, science has found that the circuitry underlying pain is astonishingly complex. Yet even the elaborate picture now revealed is not complete. Progress in the understanding of pain has depended on work in a number of scientific fields. Pharmacology, for example, has come to center stage since researchers found that nerve impulses travel by chemical means. The more that is learned about pain, the broader the scientific net that must be cast to discover the detailed mechanisms of cause, and to design successful therapies for the various kinds of pain.
Concepts Evolve Like many early scientific theories, Descartes' ideas about pain were profoundly revised in the course of later research. He had proposed a simple, direct pathway from physical injury to the pain experiellce. The first feature of the scheme to fail was the idea that one kind of pathway alone signals pain. In the late 1800s, physiologists mapped the spinothalamic (today the neospinothalamic) path along the spinal cord. They believed at first that in mapping this pathwayfrom the crossed afferent fibers of the spinothalamic tract, to the ventral nucleus of the thalamus, and from there to the somatosensory cortex-they had identified the entire pain system. Their work led physicians to treat
24
Descartes, in his 17th century "Treatise of Man," described his concept of the pain pathway, suggesting that if a noxious stimulus (A) damages the nerves, they send a pain ~essage by ~ straightforward, simple path (C) to the brain. By the 19th century, researc~ers r~alzzed. that t~lS concept was far too simple to explain the various types of sensory perceptIOn-mcludmg pam.
chronic pain by cordotomy and similar surgical procedures. Interrupting the spinothalamic pathway in this manner, it was thought, would prevent pain signals from reaching higher levels of the nervous system, where the signals are perceived. Results observed in subsequent years, however, suggested that the pain pathway in fact had not been found. Cordotomy sometimes relieved chronic pain, but pain often returned, and almost as often, the recurrent pain was more severe than the original pain.1/2 It was difficult to
reconcile these findings with the idea that the spinothalamic tract was the only messenger of pain. In the middle of this century, the new Nauta stain confirmed the pathway first marked, but it also revealed several others, including a multi synaptic pathway that ascends through the reticular formation. Researchers named this newly traced pathway the . pale 0 spinothalamic, and believed that it, together with the first-known neospinothalamic path, was the likely anatomy of the pain system. American Pharmacy Vol. NS22, No.3, March 19821136
Today, even this elaborate circuit is considered only a partial picture. Physiologists now think that at lE~ast six afferent pathways are involved in signalling pain. Such an arrangement greatly complicates the understanding of pain syndromes and the design of effective treatments.
Further Complexities Throughout the history of pain research, physiologists have proposed that some peripheral nerve receptors respond only to painful stimuli while others respond only to heat or cold or touch. This stimulus-specificity of receptors is one' possible explanation of how different kinds of environmental events cause different kinds of sensation. The idea of receptor specificity got its modern interpretation in the electrophysiological studies of Nobel laureates Gasser and Erlanger. In the 1920s they discovered that the most peripheral afferent nerve fibers could be classified by their conduction velocities. Nerve conduction velocities differ because myelinated fibers carry impulses faster than do unmyelinated fibers, and large fibers faster than fine ones. Other researchers found that the small fibers-both myelinated (Adelta) and unmyelinated (C)-respond most to noxious (normally painful) stimuli, and the large Abeta fibers respond most to touch. Receptor specificity is well established today as a general physiological fact. Not only have peripheral fibers been found that are sensitive only to touch, for example, but nearly a dozen distinct types of these so-called low-threshold mechanoreceptors have been identified .because of their special responses to vibration, movement and pressure. 3 Researchers have also found several types of pain fibers: some Adelta fiberf respond only to strong mechanical stimuli; other A-deltas respond to noxious heat as well; the C fibers respond to a variety of noxious stimuli-chemical, thermal and mechanical. While receptor specificity may explain some sensations of pain, it cannot explain some of the symptoms of chronic pain. In post-herAmerican Pharmacy Vol. NS22, No.3, March 19821137
A stalked cell is one of several kinds of cells located in the substantia gelatinosa (layer II of the spinal cord). The thicker branches toward the. bottom are dendrites which receive sensory information. Toward the top is a thinner branched axon which transmits information to higher levels of the eNS. Researchers draw pictures of these cells by hand from microscopic views of the cells to enable further study of pain pathways.
petic and trigeminal neuralgias, for example, .it is light touch, not noxious stimulation, that triggers paroxysms of pain. Similarly, phantom limb pain lacks a usual stimulus, and may persist years after injured tissue has healed and when pain receptors should not be active. Another aspect of pain that is not explained by receptor specifictty is the influence of emotion on response to pain. Beecher's classic study of men who were wounded on the field during World War II provided dramatic examples of emotion's effect on pain. Elated at escaping from battle alive, many severely wounded soldiers claimed to feel no pain at all and refused analgesic medications. 2 On a lesser scale, the severity of pain depends on its significance and on social and emotional features of the injured person's situation. These phenomena suggest that the action of specific pain receptors can only partly explain the range of pain experience. The activation of
so-called pain receptors by injury is not always accompanied by pain, nor, as chronic pain conditions demonstrate, is it necessary to activate these receptors for pain to be felt.
Contemporary Theory . Recently a gate control theory was proposed to account for these and other anomalies. 2 In outline, the theory is that certain nerve cells in the spinal cord behave like gates. The gates open when activity in small-diameter p~i mary pain-signalling fibers excites these cells, and shut when these cells are inhibited by activity in large primary afferents that ordinarily sig-· nal touch. Gate cells also can b~ inhibited by some of the many descending pathways that terminate in the spinal cord. The gate cells compute a kind of average of these various inputs and send the processed message -along with other messages of this type-on . to higher levels of
the brain where the final message is received. Gate control theory is consistent with two of the most successful ideas of modern neurophysiology: • That inhibition is as common as excitation in the normal working of the nervous system; • That sensory systems are not straight-through, passive information shunts from the world to consciousness, but rather are active processors of information, passing it through successive filters, abstracting only the most important features. This second idea explains why so much attention is given to the spinal cord in pain research: in the spinal cord are the first way stations-the first synaptic 'c onnections-at which incoming information is processed. 'Equally important, gate control theory explains psychological and physiological facts that were unexplained by traditional theory. It explains why some pain syndromes, like the post-herpetic and trigeminal neuralgias, are associated with damage to large primary afferents. The theory is that if activity in large fibers is pathologically interrupted, the fibers cannot inhibit , gate cells and, from the gate cells' point of view, signals from small pain fibers appear enhanced. Since gate cells weigh the relative activity of the two kinds of fiber, in these syndromes the cells send on a message of pain. Gate control theory might explain the common experience of being able to attenuate pain by rubbing the painful area. Exciting large touch-sensitive fibers in this way closes the gate. The theory may also provide a potential account of the more exotic results of acupuncture. Effective acupuncture points are those where large fibers predominate. 4 The stimulation of these points by needling might enhance large fiber activity and drown out the activity of small fibers that would otherwise signal pain. The gate is a mechanism that can account for the sometimes profound effects of social and emotional factors on pain: inhibitory pathways that descend from higher levels of 26
the CNS can shut the gate more or less completely depending on how a person evaluates the circumstances of his or her injury. The more recent theory has been a tremendous impulse for research and for designing pain therapies. Transcutaneous electrical stimulation (TNS) is just one suggested ,by the gate theory. About half the patients who suffer chronic pain from peripheral nerve injury respond to TNS, a therapy which seems to have no adverse effects. In its outline form, and in its emphasis on information processing and descending control, the gate theory still directs pain , research. But the results of research it has led to indicate that the theory's details must be changed.
Interdisciplinary Approach In the 1950s, Rexed mapped the complex, highly organized cytoarchitecture of the spinal cord, revealing new features of the pain circuit. He found that the spinal cord consisted of distinct layers, or laminae, each distinguished by its own kinds of nerve cells and nerve cell connections. He identified them with the Roman numerals I-X. Researchers have proposed that gate cells might be found in the superficiallayers of the dorsal horn, in Rexed's lamina II, a region corresponding roughly to that known for more than a century as the substantia gelatinosa, owing to its gelatinous appearance when observed under a light microscope. Re,c ent electrophysiological, immunocytochemical and electron microscopic research indicate, however, that this region is much more complicated than was thought when the gate theory was first proposed. These findings make it increasingly evident that understanding the circuit's numerous parts and functions will require an interdisciplinary approach. ' The neurobiology and anesthesiology branch of the National Institute of Dental Research (NIDR) at the National Institutes of Health is one laboratory that empasizes such an interdisciplinary approach in its research on pain. Its methods include clinical, psychophysical, be-
havioral, electrophysiological, and immunohistochemical techniques. Fine anatomical studies have demonstrated unexpected complexities in the region proposed as the gate. Neuroanatomists at NIDR have found that the substantia gelatinosa itself contains not one, but most likely at least five kinds of local neurons. The best characterized so far are stalked and islet cells. 5 On the basis of electron microscope and other studies of their fine features and synaptic connections, stalked cells are thought to have an excitatory role in relaying pain information, doubling back their message to lamina I from which the message travels to higher levels of the CNS. Similar studies suggest that islet , cells are inhibitory. Through the I elaborate connections they make with primary fibers, stalked cells, I and perhaps other local neurons, they are believed to playa complex, I mediating role in the processing of pain information. Dr. Stephen Gobel at NIDR believes that the substantia gelatinosa's structure is complex and regular, consisting of two distinct layers. Whatever gating occurs in the substantia gelatinosa, then, occurs in a more complicated way than researchers first thought. Identification of the substantia gelatinosa's circuit diagram is not yet complete; neither is identification of the area's functions nor their significance in terms of human experience. Here, interdisciplinary research will be required to find the answers. I
Classifying Pain Psychophysical stUdies at NIDR classify the different types of pain as they are felt, so that eventually these types can be correlated with various physiologic states of- the pain system. Correlation of psychophysical and physiological data has already suggested an explanation for some kinds of pain response. An unpleasantly hot stimulus provokes both first" and "second" pains-a sharp and well-localized pain followed by a burning diffuse sensation that follows about a second later. The latencies of first and II
American Pharmacy Vol. NS22, No.3, March 1982/138
Corticosteroids have been used in the treatment of alcoholic hepatitis with the rationale that the disease is characterized by an inflammatory process and that immunological factors may playa significant role in'its pathogenesis. The results of the clinical trials to date have been variable as to the effectiveness of corticosteroids for all degrees of severity of alcoholic hepatitis. It appears that they are most effective if given in high doses to biopsy-proven alcoholic hepatitis patients who have severe clinical symptoms.14
Alcoholic Cirrhosis The most severe form of alcoholic liver diseaseJ alcoholic cirrhosis (Laennec's cirrhosis), is irreversible. It is essentially the end-stage scar lesion of alcoholic liver disease, characterized by diffuse, nodular fibrosis surrounding areas of normal or regenerated hepatic tissue. This results in alteration of the normal hepatic architecture and a decrease in the ability of the liver to perform its metabolic functions. The scarring of alcoholic cirrhosis is generally believed to be a reaction to the hepatocyte necrosis and inflammation of alcoholic hepatitis. The immunologic response that is thought to be significant in the pathogenesis of alcoholic hepatitis may also cause progression to cirrhosis. 15 This mechanism may be responsible for those alcoholic hepatitis patients who, despite abstinence from alcohol, develop cirrhosis. Yet, additional pathways must also exist in the pathogenesis of alcoholic cirrhosis because the disease has been demonstrated to develop without any apparent intermediate alcoholic hepatitis stage. 16 One possible explanation is that collagen production is stimulated in the hepatocyte as a result of the metabolism of alcohol. It is hypothesized that because of this stimulated collagen production, accumulation occurs within the hepatocyte with eventual fibrosis ensuing. Whatever the pathogenesis of alcoholic cirrhosis, the major clinical manifestations and sequelae of the disease are a consequence of the American Pharmacy Vol. NS22, No. 4, April 19821195
eventual impaired liver functions ' erally thought to be irreversible. and of the disrupted architecture Therefore, the goals of therapy are (see box above). not to reverse the pathologic process, but to prevent the progression One major function of the normal liver that is altered in' the cirrhotic . of the disease and manage the disease complications. patient is its ability to metabolize potentially harmful substances. The two most frequent causes of Thus, the metabolism of exogenous death in patients with cirrhosis are substances, such as drugs or ingastrointestinal bleeding (from esophageal varices) and complete gested toxins, as well as endoliver failure (hepatic coma). genous substances, such as estroIt has been shown that although gens, aldosterone, bilirubin, and the disease is irreversible once pabiogenic amines, is impaired. thologic changes have occurred, the The resulting excesses of these five-year survival rate is significantsubstances are responsible for the ly increased in those patients who following clinical manifestations: abstain from alcohol and undergo feminization characteristics, sodium aggressive supportive management and water retention which conof these disease complications. 17 0 tributes to peripheral edema and ascites formation, jaundice, and hepatic coma. References Additionally, the liver is normally 1. H. G, Zimmerman, "Hepatotoxicity: Adverse Effects responsible for the production of of Drugs and Other Chemicals on the Liver," Appleton-Century Crofts, New York, 1978. certain coagulation factors and vas2. C. S. · Lieber and E. Rubin, American Journal of Medicine, 44, 200 (1968). cular proteins. Decreases in their 3. C. S. Lieber, Clinics in Gastroenterology, 10, 315 (1981). prod uction are characterized by a 4. H . D. Lipsitz, et al., Gastroenterology, 81, 594 (1981). 5. J. T. Galambos, Gastroenterology, 63, 1026 (1972). hemorrhagic tendency in the pa6. K. C. Gaines and M. F. Sorrell, Medical Clinics of tient, and contribute to ascites and North America, 63, 495 (1979). 7. K. J. Isselbacher, Nw England Journal of Medicine, 296, peripheral edema. 612 (1977). 8. O . Johnson, Scandinavian Journal of Gastroenterology, 2, The major sequela of a disrupted 207 (1974). hepatic architecture is portal venous 9. C. S. Lieber and R. Schmid , Journal of Clinical Investigation, 40, 394 (1961). hypertension which develops sec10. E. Baraona, et al., Journal of Clinical Investigation, 60, ondary to obstructed blood flow 546 (1977). 11. P. B. Beeson, W. McDermott and J. B. Wyngaarden, within the liver. This obstruction reeds. , " Textbook of Medicine, 15th Edition," W. B. sults not only in the clinical manSaunders Co., Philadelphia, 1979. 12. S. M. Sabesin, et al. , Gastroenterology, 74, 276 (1978). ifestations of a swollen portal ve13. C. L. Mendenhall, et al. , Clinics in Gastroenterology, 10, nous system (esophageal varices 417 (1981). W. C. Maddrey, et al., Gastroenterology, 75, 193 (1978). and splenomegaly), but also in de- _ 14. 15. S. Kakumu and C. M. Leevy, Gastroenterology, 72, 594 (1977). creased deliverance of potential tox16. H. Popper and C. S. Lieber, American Journal of Pathins to the liver for metabolism. ology, 98, 695 (1980). 17. M. M. Figler and J. G. Rankin, eds., " Alcohol and The fibrotic changes that characthe Liver," Plenum Press, New York, 1976. terize alcoholic cirrhosis are gen-
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The significance of this finding is that, even at the level of the spinal cord, it is not just the physical value of a stimulus that determines whether nerve cells will fire, but also what the stimulus means. Information is apparently filtered very early in the sensory process depending on what it has come to indicate about other environmental events. Descending inhibitory pathways probably function as a screen so the animal can focus on just those events most important for survival. This highly adaptive mechanism may be clarified in other studies at NIDR. Researchers there are using electrophysiological methods to study pathways that descend to pain cells in the spinal cord. One major pathway projects from the nucleus raphe magnus in the midbrain through the dorsal horn. Researchers have found that cells in this area (dorsal horn) of the spinal cord that respond to noxious stimuli can be shut down by stimulating cells in the nucleus raphe magnus. This finding indicates that the nucleus's natural function is to inhibit ' pain messages; perhaps it provides a mechanism through which emotional and motivational influences act.
Neuropharmacology Another major area of research at NIDR concentrates on the rapidly growing field of neuropharmacology and the actions of neurotransmitters and neuromodulators in pain pathways. Immunocytochemical and autoradiographic studies of the dorsal horn have revealed an abundance of different possible transmitting substances in its superficial layers. Enkephalin, cholecystokinin, Substance P, and somatostatin (found throughout the CNS) are among those localized in the hypothetical gate region. Pain researchers know that enkephalin depresses pain-signaling cells, possibly by the same mechanism that morphine does: its action on pain cells-like that of morphine -is antagonized by naloxone. Somatostatin is another endogenous substance that inhibits pain, but its effect is not counteracted by nalox-
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one; thus, knowing somatostatin's mode of action could provide the basis for developing non-narcotic analgesic agents. Similarly, study of excitatory substances in the pain system, like Substance P, may lead to the design of new pharmacological agents for pain treatments. If Substance P is a principal chemical messenger of pain, knowing its manner of action will enable researchers to design drugs to interrupt that action at some point, thus alleviating pain. Understanding the physiological action of neurotransmitters and neuromodulators has required the development of elegant techniques, several of which are used at NIDR.
Research on the physiology and neurochemistry of pain should lead to drugs that are more effective . ..
For example, in micro iontophoresis, minute amounts of putative transmitter substances are placed near individual cells by specially designed microscopic equipment. The effect of the substance on a cell is measured and compared to that cell' s response to noxious stimuli. If the substance affects the cell in the same way that natural stimulati<;m does, it is considered as the chemical messenger for that link of the pain circuit. New in vitro studies also provide an opportunity to observe the effects of different substances on nerve cells in ionically controlled microenvironments . For example, normal synaptic action requires the presence of calcium. A substance may be applied to a cell in a calciumfree environment to determine whether the substance acts directly or by presynaptic mediation. One other puzzle arose from the gate theory as it was originally proposed: a few large fibers respond to noxious stimuli and quite a number of small fibers respond to touch, contrary to the general rule. This paradox might be resolved by neuropharmacological research, if pain
fibers could be classified by their neurotransmitters rather than by their size or electrical properties. This may be found to be true, but as has happened so many times before, investigators have revealed a new twist in an already tangled story-many fibers contain more than one neurotransmitter.
New Drugs It may seem that basic research on pain only poses more and more new puzzles; but it also has resolved a few. The new nonsteroidal anti-inflammatory agents, for example, were devised specifically as a result of basic research. Investigators knew that prostaglandins were released at the periphery by damaged tissue and that they hypersensitized pain fibers. So, molecular engineers set out to design agents to interfere with prostaglandin release . The drugs that resulted include . zomepirac sodium, ibuprofen arid sodium naproxin. These drugs have proved to be highly effective analgesic agents for a wide variety of pain conditions, including dysmenorrhea and the chronic pain of osteoarthritis and cancer. Zomepirac sodium, in particular, is as powerful as usual doses of codeine and other narcotics. Yet these agents are not addictive, and patients don't develop tolerance to them even after extensive use. No doubt, through further basic research on the physiology and neurochemistry of pain, new pharmacological agents can be designed for currently intractable pain. Such research should eventually lead to drugs that are even more effective, specific and benign. -Ann Covalt American Pharmacy correspondent
References 1. H. C. Voris and W. W. Whisler (eds.), "Trea tment of Pain," Charles Thomas, Springfield, IL, 1975.
2. R. Melzack, "The Puzzle of Pain," Basic Books, Inc., New York, 1973. 3. j . Bonica (ed .), "Pain, Discomfo rt and Humanitarian Care, " Elsevier North Holland, Inc., Amsterdam, 1980. 4. Lu Guowei el al., Chinese Medical Journal, 94, 255 (1981).
5. S. Gobel el al., The Journal of Comparalive Neurology, 194, 781 (1980).
6. R. Melzack, Pain 1, 277 (1975). 7. R. Dubner, D. S. Hoffman and R. L Hayes, Journal of Neurophysiology (in press).
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