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Pain Terminology as it Applies to Animal Experiments
Commentary
Pain Terminology as It Applies to Animal Experiments William D. Willis
he Focus article by Drs. Chaplan and Sorkin appropriately calls attention to a problem in pain medicine and pain research, the difficulty in defining and agreeing to pain terminology. Some of the particular issues that were raised by the authors or by members of the pain research community who were surveyed by the authors are (1) the use of words that might be regarded as jargon; (2) the use of words that do not correspond to what is currently known about the neural systems or mechanisms of a particular pain state; (3) the officialization of terms by scientific organizations; (4) the so-far poor dispersion of recently defined terms among clinicians, patients, and research personnel, including prominent members of the pain research community and even journal editors; (5) overt hostility by some users toward particular terms; (6) a lack of operational utility of some terms; (7) the need for a clear terminology that can be used for diagnostic coding to allow reimbursement for treatment of pain; (8) the idea that terms should be informative and not seem pejorative to patients; and (9) the need for correspondence between words describing clinical states and words applied by basic researchers to animal models of disease. Presumably, other Commentaries will discuss the use of pain terminology in a clinical setting. As my laboratory is engaged in basic, rather than clinical, research, this Commentary emphasizes the use of pain terms in animal experiments.
T
PAIN IN ANIMALS Although animals cannot verbalize the presence of pain, there is no doubt that animals experience pain; From the Department of Anatomy & Neurosciences, University of Texas Medical Branch, Galveston, TX. Reprint requests: Wm. D.Willis, MD, Department of Anatomy & Neurosciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069.
88
however, most pain research in animals uses tests of flexor withdrawal reflexes or of such behaviors as paw licking and vocalization in response to transient noxious stimuli rather than attempts to evaluate ongoing pain. Exceptions are studies of autotomy [14,21] and of ongoing pain in models of neuropathic pain [2,6]. When pain is inferred to be occurring in animals, the observer may choose to state the opinion that pain is present, and this can be supported by ancillary evidence, such as the diminution of the apparent pain following administration of an analgesic drug or some other therapeutic manipulation known to relieve pain in human subjects [20]. More often, however, pain researchers choose to describe behaviors that are said to be nociceptive or nocifensive, such as a flexor withdrawal reflex, and then to use the term antinociceptive when a therapeutic manipulation diminishes the response or elevates its threshold. These behaviors would not generally correspond to ongoing pain in humans, but would rather reflect evoked pain, such as allodynia or hyperalgesia of either the primary or secondary type [7]. Unfortunately, no distinction is made between primary and secondary hyperalgesia in the International Association for the Study of Pain (IASP) list of pain terms [18]. And yet from a mechanistic perspective, such a distinction would provide a valuable link between findings in animal research and clinical applications.
PRIMARY HYPERALGESIA In humans, hyperalgesia is defined by the IASP Committee on Nomenclature as an increased response to a stimulus that is normally painful [18]. Primary hyperalgesia is hyperalgesia in an area of injury [11-21,25]. Animal experiments reveal that the discharges of nociceptive primary afferent fibers are increased in response to a given intensity of noxious stimulus following injury [13,19]. The increased responsiveness of the nociceptive afferents is linked to the process of "primary afferent sensitization" that results from an interaction of
Pain Forum 6(2): 88-91, 1997
COMMENTARY/Willis
a number of inflammatory mediators with receptor molecules on the peripheral terminals of the nociceptors [12] and the subsequent activation of intracellular signal transduction pathways in these nerve fibers [10]. The result is an enhancement in the sensitivity of the nociceptors and a consequently greater discharge of individual afferents and activation of a larger population of nociceptors by a given noxious stimulus following an injury than before injury. A source of confusion is that the thresholds of nociceptors can be lowered in hyperalgesia to the point that they overlap with the thresholds of sensitive mechano- or thermoreceptors [11], and so it would often be difficult to distinguish between allodynia and hyperalgesia if hyperalgesia were defined in terms of a lowered threshold for pain. In research done on awake, behaving animals, a case can be made that when a stimulus that normally results in a nociceptive response causes an increased response when applied to an injured area, the animal can be interpreted to display primary hyperalgesia. In anesthetized or decerebrate animals, recordings of increased discharges in primary afferent nociceptors or in central nociceptive neurons following stimulation of an injured area can be suggested to reflect the primary hyperalgesia that would have been present had the animal been conscious. The changes in neural discharges in such experiments represent a model system that allows the investigation of possible mechanisms that underlie primary hyperalgesia, even though the animal is unconscious. The advantage of this approach is that cellular and even molecular processes can be analyzed while retaining a linkage to behavior. As suggested in the Focus article, therapies that normalize hyperalgesia can be termed antihyperalgesic procedures.
SECONDARY HYPERALGESIA AND ALLODYNIA When used in reference to the skin, secondary hyperalgesia is hyperalgesia that can be demonstrated by stimulation of an uninjured region adjacent to an area of damage [11,12,25]. Presumably, pain referral in diseases of muscle or viscera is a similar phenomenon. The tissue that hurts is not that which is damaged. Allodynia is pain caused by a stimulus that does not normally provoke pain [18]. As pointed out in the Focus article, this implies a change in sensory modality. For example, mechanical allodynia is provoked by a stimulus that is normally tactile, and the primary afferent fibers that transmit the sensory input are A~-fibers [3,12]. Similarly, thermal allodynia would be provoked by stimulation of afferents supplying specific thermoreceptors, either cold or warm fibers.
89
A number of investigations have led to the conclusion that secondary hyperalgesia and allodynia depend on changes in the central nervous system that lead to increases in the responsiveness of nociceptive neurons in the spinal cord or medullary dorsal horn or at higher levels of the central nervous system [6,9,22]. The central changes are not secondary to changes in the responsiveness of peripheral nerve fibers, as proposed by Lewis [15], because it has been shown that there are no changes in the response properties of afferents supplying the area of secondary hyperalgesia or allodynia [17]. The elegant experiment of Torebjork et al. provides further evidence that allodynia does not depend on peripheral changes in sensory transduction, but rather on central changes [24]. They placed a microneurography needle in a peripheral nerve in a conscious human subject. Stimulation through the microelectrode evoked a sensation of touch that was projected to a peripheral receptive field. Allodynia developed following intradermal injection of capsaicin into an area of skin separated from the projected receptive field by a sufficient distance that the capsaicin would not affect the responsiveness of afferent fibers supplying the receptive field. The sensation depended on electrical stimulation of tactile afferents in the peripheral nerve, not on stimulation of the skin, and so changes in the properties of the sensory terminals played no role in the altered sensory experience. Later, when the area of secondary hyperalgesia and allodynia spread to include the projected receptive field, stimulation in the nerve with the same stimulus parameters as before resulted in pain. That is, tactile afferents now evoked pain. When the area of secondary hyperalgesia and allodynia receded away from the projected receptive field, electrical stimulation in the nerve no longer caused pain but only touch. Clearly, the change in quality of the sensory response must have depended on changes in the central nervous system. Direct evidence that secondary hyperalgesia and allodynia result from a prolonged change in the responsiveness of dorsal horn neurons, but not in the responsiveness of primary afferent neurons, comes from animal experiments. In an experimental model that involves intradermal injection of capsaicin, the excitability of afferents that supply the area of secondary hyperalgesia and allodynia was shown not to change following intradermal injection of capsaicin [7]. On the other hand, the responsiveness of central neurons, such as spinothalamic tract cells, does change [9,22]. For example, the number of discharges of spinothalamic tract neurons evoked by volleys elicited by electrical stimulation of the proximal stump of a cut dorsal root filament increases following intradermal injection of capsaicin [22]. Furthermore, the responses of spinothalamic tract cells to ion-
90
COMMENTARY/Willis
tophoretically released excitatory amino acids increases after intradermal injection of capsaicin [9]. Although these enhanced responses could reflect an increased background excitability of the spinothalamic tract cells caused by continuous input from peripheral nociceptors following capsaicin administration, it appears that primary afferent nociceptors do not continue to discharge for more than a short time after stimulation by capsaicin; indeed, many nociceptors become desensitized and cease discharging [2]. This suggests that the prolonged change in responsiveness of dorsal horn neurons is due to a form of central plasticity. This process has been designated central sensitization and appears to result from combined release of glutamate and peptides, such as substance P, and activation of signal transduction pathways in dorsal horn neurons [6,8,16]. Other mechanisms may also contribute to central sensitization. For example, there is a reduction in the inhibitory responses of spinothalamic tract cells during central sensitization [17], and so this form of sensitization may reflect not only an increase in excitation but also a reduction in inhibition. Still another mechanism may be the triggering of dorsal root reflexes in C-fibers by volleys in Ap-fibers, leading to the activation of nociceptive neurons by tactile afferents [4]. Plastic changes at levels of the nervous system higher than the spinal cord may also contribute to secondary hyperalgesia and allodynia. In awake, behaving animals, it seems plausible to describe an increase in nociceptive responses to noxious stimuli in terms of secondary hyperalgesia and an increase in nociceptive responses to normally tactile stimuli in terms of allodynia [7,23]. In anesthetized or decerebrate animal models, it seems appropriate to suggest that increases in central nociceptive neuronal responses to noxious stimuli applied to undamaged tissue accompany secondary hyperalgesia and that increases in responses of central nociceptive neurons to weak mechanical or thermal stimuli applied to undamaged areas accompany allodynia [19,22]. As suggested in the Focus article, therapies that normalize allodynia could reasonably be called antiallodynic. Although this may not be the rationale for use of a particular drug at present, it may become so. A controversial issue is the role of wide-dynamicrange nociceptive neurons in allodynia. If the responses of such neurons signal pain alone, and if their responses to tactile stimuli are normally small enough not to exceed some central threshold for pain [12], then these neurons would have a normal function not unlike that of highthreshold or nociceptive-specific neurons [26]. If the responses to tactile stimuli become enhanced following injury to an area adjacent to the receptive field, and if the responses now exceed the central threshold for
pain, then wide-dynamic-range neurons could help account for mechanical allodynia. It is, however, conceivable that these cells contribute to tactile sensations, as well as to pain, through some form of population coding.
WHAT CAN BE DONE TO IMPROVE THE USAGE OF PAIN TERMS? Although pain terms generally originate from descriptions of abnormal sensations by patients, basic research can shed light on mechanisms underlying these abnormal sensations. It seems reasonable to expect that feedback from the bench about mechanistic explanations of abnormal sensory experience will improve clinical understanding, influence the diagnosis of pain states, and mold terminology. The Focus article concludes with the statement that "we need a common language" and a plea that this could be encouraged by the following actions. Reviewers of papers in the pain field should be reminded of the definitions of pain terms, so that journal articles use these consistently. Attention should be given to the use of pain terms in the medical school curriculum and in postgraduate education to ensure that medical students and house staff learn about pain and pain nomenclature. Finally, there should be increased usage of pain terms in the general media. Clearly, scientific and professional organizations, such as the American Pain Society and the IASP, can playa key role in these educational efforts. In addition, it appears that basic science studies should provide evidence for the mechanisms responsible for the pain states described by the pain terminology, and clinical research should be done to verify that the mechanisms studied in animal experiments apply to humans. Furthermore, the IASP list of pain terminology should be expanded to include the concepts of primary and secondary hyperalgesia.
References 1. Baumann TK, Simone DA, Shain CN, LaMotte RH: Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J NeurophysioI66:212-227, 1991 2. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107,1988 3. Campbell IN, Raja SN, Meyer RA, Mackinnon SE: Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89-94, 1988 4. Cervero F, Laird JMA: Mechanisms of touch-evoked pain (allodynia): a new model. Pain 68:13-23, 1996
COMMENTARY/Willis
91
5. Choi Y, Yoon YW, Na HS et al: Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59:369-376, 1994
15. Lewis T: Pain. MacMillan, London, 1942 16. Lin 0, Peng YB, Willis WD: Possible role of protein kinase
6. Coderre TJ, Katz J, Vaccarino AL, Melzack R: Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 52:259-285,
17. Lin Q, Peng YB, Willis WD: Inhibition of primate spinothal-
1993 7. Cui JG, Linderoth B, Meyerson BA: Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms: an experimental study in the mononeuropathic rat. Pain 66:287-295,1996 8. Dougherty PM, Willis WD: Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of Nmethyl-D-aspartic acid and substance P. Pain 47:85-93,
1991 9. Dougherty PM, Willis WD: Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. Neurosci 12:883-894, 1992
10. Dray A, Bettaney J, Forster P, Perkins MN: Bradykinin-
C in the sensitization of primate spinothalamic tract neurons. J Neurosci 16:3026-3034, 1996 amic tract neurons by spinal glycine and GABA is reduced during central sensitization. J Neurophysiol
76:1005-1014,1996 18. Merskey H, Bogduk N: Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. IASP, Seattle, 1994
19. Meyer RA, Campbell IN: Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science 213:1527-1529,1981
20. Puke MJC, Xu XJ, Wiesenfeld-Hallin Z: Intrathecal administration of clonidine suppresses autotomy, a behavioral sign of chronic pain in rats after sciatic nerve section. Neurosci Lett 133:199-202,1991
21. saade NE, Ibrahim MZM, Atweh SF, Jabbur SJ: Explosive autotomy induced by simultaneous dorsal column lesion and limb denervation: a possible model for acute deafferentation pain. Exp Neurol 119:272-279, 1993
induced stimulation of afferent fibres is mediated through protein kinase C. Neurosci Lett 91:301-307,1988
22. Simone DA, Sorkin LS, Oh U et al: Neurogenic hyperal-
11. Hardy JD, Wolff HG, Goodell H: Pain Sensations and Reactions. Hafner, New York, 1967 (reprinted from Williams & Wilkins, 1952) 12. Koltzenburg M: Afferent mechanisms mediating pain and hyperalgesia in neuralgia. p. 123. In JOnig W, Stanton-
gesia: central nueral correlates in responses of spinothalamic tract neurons. J Neurophysiol 66:228-246, 1991 23. Sluka KA, Westlund KN: Behavioral and immunohistochemical changes in an experimental arthritis model in rats. Pain 55:367-377,1993
Hicks M (eds): Progress in pain research and management vol. 6: Reflex sympathetic dystrophy: a reappraisal. IASP, Seattle, 1996
24. Torebjork HE, Lundberg LER, LaMotte RH: Central
13. LaMotte RH, Thalhammer JG, Torebjork HE, Robinson CJ: Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. J Neurosci 2:765-781,
1982 14. Levitt M: Dysesthesias and self-mutilation in humans and subhumans: a review of clinical and experimental studies. Brain Res Rev 10:247-290,1985
changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 448:765-780, 1992
25. Willis WD (ed): Hyperalgesia and allodynia. LippincottRaven, New York, 1992 26. Willis WD: Central plastic responses to pain. p. 301. In Gebhart GF, Hammond OL, Jensen TS (eds): Progress in Pain Research and Management, vol. 2. IASP, Seattle,
1994
Pain Terminology as It Applies to Animal Experiments William D. Willis
he Focus article by Drs. Chaplan and Sorkin appropriately calls attention to a problem in pain medicine and pain research, the difficulty in defining and agreeing to pain terminology. Some of the particular issues that were raised by the authors or by members of the pain research community who were surveyed by the authors are (1) the use of words that might be regarded as jargon; (2) the use of words that do not correspond to what is currently known about the neural systems or mechanisms of a particular pain state; (3) the officialization of terms by scientific organizations; (4) the so-far poor dispersion of recently defined terms among clinicians, patients, and research personnel, including prominent members of the pain research community and even journal editors; (5) overt hostility by some users toward particular terms; (6) a lack of operational utility of some terms; (7) the need for a clear terminology that can be used for diagnostic coding to allow reimbursement for treatment of pain; (8) the idea that terms should be informative and not seem pejorative to patients; and (9) the need for correspondence between words describing clinical states and words applied by basic researchers to animal models of disease. Presumably, other Commentaries will discuss the use of pain terminology in a clinical setting. As my laboratory is engaged in basic, rather than clinical, research, this Commentary emphasizes the use of pain terms in animal experiments.
T
PAIN IN ANIMALS Although animals cannot verbalize the presence of pain, there is no doubt that animals experience pain; From the Department of Anatomy & Neurosciences, University of Texas Medical Branch, Galveston, TX. Reprint requests: Wm. D.Willis, MD, Department of Anatomy & Neurosciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1069.
88
however, most pain research in animals uses tests of flexor withdrawal reflexes or of such behaviors as paw licking and vocalization in response to transient noxious stimuli rather than attempts to evaluate ongoing pain. Exceptions are studies of autotomy [14,21] and of ongoing pain in models of neuropathic pain [2,6]. When pain is inferred to be occurring in animals, the observer may choose to state the opinion that pain is present, and this can be supported by ancillary evidence, such as the diminution of the apparent pain following administration of an analgesic drug or some other therapeutic manipulation known to relieve pain in human subjects [20]. More often, however, pain researchers choose to describe behaviors that are said to be nociceptive or nocifensive, such as a flexor withdrawal reflex, and then to use the term antinociceptive when a therapeutic manipulation diminishes the response or elevates its threshold. These behaviors would not generally correspond to ongoing pain in humans, but would rather reflect evoked pain, such as allodynia or hyperalgesia of either the primary or secondary type [7]. Unfortunately, no distinction is made between primary and secondary hyperalgesia in the International Association for the Study of Pain (IASP) list of pain terms [18]. And yet from a mechanistic perspective, such a distinction would provide a valuable link between findings in animal research and clinical applications.
PRIMARY HYPERALGESIA In humans, hyperalgesia is defined by the IASP Committee on Nomenclature as an increased response to a stimulus that is normally painful [18]. Primary hyperalgesia is hyperalgesia in an area of injury [11-21,25]. Animal experiments reveal that the discharges of nociceptive primary afferent fibers are increased in response to a given intensity of noxious stimulus following injury [13,19]. The increased responsiveness of the nociceptive afferents is linked to the process of "primary afferent sensitization" that results from an interaction of
Pain Forum 6(2): 88-91, 1997
COMMENTARY/Willis
a number of inflammatory mediators with receptor molecules on the peripheral terminals of the nociceptors [12] and the subsequent activation of intracellular signal transduction pathways in these nerve fibers [10]. The result is an enhancement in the sensitivity of the nociceptors and a consequently greater discharge of individual afferents and activation of a larger population of nociceptors by a given noxious stimulus following an injury than before injury. A source of confusion is that the thresholds of nociceptors can be lowered in hyperalgesia to the point that they overlap with the thresholds of sensitive mechano- or thermoreceptors [11], and so it would often be difficult to distinguish between allodynia and hyperalgesia if hyperalgesia were defined in terms of a lowered threshold for pain. In research done on awake, behaving animals, a case can be made that when a stimulus that normally results in a nociceptive response causes an increased response when applied to an injured area, the animal can be interpreted to display primary hyperalgesia. In anesthetized or decerebrate animals, recordings of increased discharges in primary afferent nociceptors or in central nociceptive neurons following stimulation of an injured area can be suggested to reflect the primary hyperalgesia that would have been present had the animal been conscious. The changes in neural discharges in such experiments represent a model system that allows the investigation of possible mechanisms that underlie primary hyperalgesia, even though the animal is unconscious. The advantage of this approach is that cellular and even molecular processes can be analyzed while retaining a linkage to behavior. As suggested in the Focus article, therapies that normalize hyperalgesia can be termed antihyperalgesic procedures.
SECONDARY HYPERALGESIA AND ALLODYNIA When used in reference to the skin, secondary hyperalgesia is hyperalgesia that can be demonstrated by stimulation of an uninjured region adjacent to an area of damage [11,12,25]. Presumably, pain referral in diseases of muscle or viscera is a similar phenomenon. The tissue that hurts is not that which is damaged. Allodynia is pain caused by a stimulus that does not normally provoke pain [18]. As pointed out in the Focus article, this implies a change in sensory modality. For example, mechanical allodynia is provoked by a stimulus that is normally tactile, and the primary afferent fibers that transmit the sensory input are A~-fibers [3,12]. Similarly, thermal allodynia would be provoked by stimulation of afferents supplying specific thermoreceptors, either cold or warm fibers.
89
A number of investigations have led to the conclusion that secondary hyperalgesia and allodynia depend on changes in the central nervous system that lead to increases in the responsiveness of nociceptive neurons in the spinal cord or medullary dorsal horn or at higher levels of the central nervous system [6,9,22]. The central changes are not secondary to changes in the responsiveness of peripheral nerve fibers, as proposed by Lewis [15], because it has been shown that there are no changes in the response properties of afferents supplying the area of secondary hyperalgesia or allodynia [17]. The elegant experiment of Torebjork et al. provides further evidence that allodynia does not depend on peripheral changes in sensory transduction, but rather on central changes [24]. They placed a microneurography needle in a peripheral nerve in a conscious human subject. Stimulation through the microelectrode evoked a sensation of touch that was projected to a peripheral receptive field. Allodynia developed following intradermal injection of capsaicin into an area of skin separated from the projected receptive field by a sufficient distance that the capsaicin would not affect the responsiveness of afferent fibers supplying the receptive field. The sensation depended on electrical stimulation of tactile afferents in the peripheral nerve, not on stimulation of the skin, and so changes in the properties of the sensory terminals played no role in the altered sensory experience. Later, when the area of secondary hyperalgesia and allodynia spread to include the projected receptive field, stimulation in the nerve with the same stimulus parameters as before resulted in pain. That is, tactile afferents now evoked pain. When the area of secondary hyperalgesia and allodynia receded away from the projected receptive field, electrical stimulation in the nerve no longer caused pain but only touch. Clearly, the change in quality of the sensory response must have depended on changes in the central nervous system. Direct evidence that secondary hyperalgesia and allodynia result from a prolonged change in the responsiveness of dorsal horn neurons, but not in the responsiveness of primary afferent neurons, comes from animal experiments. In an experimental model that involves intradermal injection of capsaicin, the excitability of afferents that supply the area of secondary hyperalgesia and allodynia was shown not to change following intradermal injection of capsaicin [7]. On the other hand, the responsiveness of central neurons, such as spinothalamic tract cells, does change [9,22]. For example, the number of discharges of spinothalamic tract neurons evoked by volleys elicited by electrical stimulation of the proximal stump of a cut dorsal root filament increases following intradermal injection of capsaicin [22]. Furthermore, the responses of spinothalamic tract cells to ion-
90
COMMENTARY/Willis
tophoretically released excitatory amino acids increases after intradermal injection of capsaicin [9]. Although these enhanced responses could reflect an increased background excitability of the spinothalamic tract cells caused by continuous input from peripheral nociceptors following capsaicin administration, it appears that primary afferent nociceptors do not continue to discharge for more than a short time after stimulation by capsaicin; indeed, many nociceptors become desensitized and cease discharging [2]. This suggests that the prolonged change in responsiveness of dorsal horn neurons is due to a form of central plasticity. This process has been designated central sensitization and appears to result from combined release of glutamate and peptides, such as substance P, and activation of signal transduction pathways in dorsal horn neurons [6,8,16]. Other mechanisms may also contribute to central sensitization. For example, there is a reduction in the inhibitory responses of spinothalamic tract cells during central sensitization [17], and so this form of sensitization may reflect not only an increase in excitation but also a reduction in inhibition. Still another mechanism may be the triggering of dorsal root reflexes in C-fibers by volleys in Ap-fibers, leading to the activation of nociceptive neurons by tactile afferents [4]. Plastic changes at levels of the nervous system higher than the spinal cord may also contribute to secondary hyperalgesia and allodynia. In awake, behaving animals, it seems plausible to describe an increase in nociceptive responses to noxious stimuli in terms of secondary hyperalgesia and an increase in nociceptive responses to normally tactile stimuli in terms of allodynia [7,23]. In anesthetized or decerebrate animal models, it seems appropriate to suggest that increases in central nociceptive neuronal responses to noxious stimuli applied to undamaged tissue accompany secondary hyperalgesia and that increases in responses of central nociceptive neurons to weak mechanical or thermal stimuli applied to undamaged areas accompany allodynia [19,22]. As suggested in the Focus article, therapies that normalize allodynia could reasonably be called antiallodynic. Although this may not be the rationale for use of a particular drug at present, it may become so. A controversial issue is the role of wide-dynamicrange nociceptive neurons in allodynia. If the responses of such neurons signal pain alone, and if their responses to tactile stimuli are normally small enough not to exceed some central threshold for pain [12], then these neurons would have a normal function not unlike that of highthreshold or nociceptive-specific neurons [26]. If the responses to tactile stimuli become enhanced following injury to an area adjacent to the receptive field, and if the responses now exceed the central threshold for
pain, then wide-dynamic-range neurons could help account for mechanical allodynia. It is, however, conceivable that these cells contribute to tactile sensations, as well as to pain, through some form of population coding.
WHAT CAN BE DONE TO IMPROVE THE USAGE OF PAIN TERMS? Although pain terms generally originate from descriptions of abnormal sensations by patients, basic research can shed light on mechanisms underlying these abnormal sensations. It seems reasonable to expect that feedback from the bench about mechanistic explanations of abnormal sensory experience will improve clinical understanding, influence the diagnosis of pain states, and mold terminology. The Focus article concludes with the statement that "we need a common language" and a plea that this could be encouraged by the following actions. Reviewers of papers in the pain field should be reminded of the definitions of pain terms, so that journal articles use these consistently. Attention should be given to the use of pain terms in the medical school curriculum and in postgraduate education to ensure that medical students and house staff learn about pain and pain nomenclature. Finally, there should be increased usage of pain terms in the general media. Clearly, scientific and professional organizations, such as the American Pain Society and the IASP, can playa key role in these educational efforts. In addition, it appears that basic science studies should provide evidence for the mechanisms responsible for the pain states described by the pain terminology, and clinical research should be done to verify that the mechanisms studied in animal experiments apply to humans. Furthermore, the IASP list of pain terminology should be expanded to include the concepts of primary and secondary hyperalgesia.
References 1. Baumann TK, Simone DA, Shain CN, LaMotte RH: Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J NeurophysioI66:212-227, 1991 2. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87-107,1988 3. Campbell IN, Raja SN, Meyer RA, Mackinnon SE: Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89-94, 1988 4. Cervero F, Laird JMA: Mechanisms of touch-evoked pain (allodynia): a new model. Pain 68:13-23, 1996
COMMENTARY/Willis
91
5. Choi Y, Yoon YW, Na HS et al: Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59:369-376, 1994
15. Lewis T: Pain. MacMillan, London, 1942 16. Lin 0, Peng YB, Willis WD: Possible role of protein kinase
6. Coderre TJ, Katz J, Vaccarino AL, Melzack R: Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 52:259-285,
17. Lin Q, Peng YB, Willis WD: Inhibition of primate spinothal-
1993 7. Cui JG, Linderoth B, Meyerson BA: Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms: an experimental study in the mononeuropathic rat. Pain 66:287-295,1996 8. Dougherty PM, Willis WD: Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of Nmethyl-D-aspartic acid and substance P. Pain 47:85-93,
1991 9. Dougherty PM, Willis WD: Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. Neurosci 12:883-894, 1992
10. Dray A, Bettaney J, Forster P, Perkins MN: Bradykinin-
C in the sensitization of primate spinothalamic tract neurons. J Neurosci 16:3026-3034, 1996 amic tract neurons by spinal glycine and GABA is reduced during central sensitization. J Neurophysiol
76:1005-1014,1996 18. Merskey H, Bogduk N: Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. IASP, Seattle, 1994
19. Meyer RA, Campbell IN: Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science 213:1527-1529,1981
20. Puke MJC, Xu XJ, Wiesenfeld-Hallin Z: Intrathecal administration of clonidine suppresses autotomy, a behavioral sign of chronic pain in rats after sciatic nerve section. Neurosci Lett 133:199-202,1991
21. saade NE, Ibrahim MZM, Atweh SF, Jabbur SJ: Explosive autotomy induced by simultaneous dorsal column lesion and limb denervation: a possible model for acute deafferentation pain. Exp Neurol 119:272-279, 1993
induced stimulation of afferent fibres is mediated through protein kinase C. Neurosci Lett 91:301-307,1988
22. Simone DA, Sorkin LS, Oh U et al: Neurogenic hyperal-
11. Hardy JD, Wolff HG, Goodell H: Pain Sensations and Reactions. Hafner, New York, 1967 (reprinted from Williams & Wilkins, 1952) 12. Koltzenburg M: Afferent mechanisms mediating pain and hyperalgesia in neuralgia. p. 123. In JOnig W, Stanton-
gesia: central nueral correlates in responses of spinothalamic tract neurons. J Neurophysiol 66:228-246, 1991 23. Sluka KA, Westlund KN: Behavioral and immunohistochemical changes in an experimental arthritis model in rats. Pain 55:367-377,1993
Hicks M (eds): Progress in pain research and management vol. 6: Reflex sympathetic dystrophy: a reappraisal. IASP, Seattle, 1996
24. Torebjork HE, Lundberg LER, LaMotte RH: Central
13. LaMotte RH, Thalhammer JG, Torebjork HE, Robinson CJ: Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. J Neurosci 2:765-781,
1982 14. Levitt M: Dysesthesias and self-mutilation in humans and subhumans: a review of clinical and experimental studies. Brain Res Rev 10:247-290,1985
changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 448:765-780, 1992
25. Willis WD (ed): Hyperalgesia and allodynia. LippincottRaven, New York, 1992 26. Willis WD: Central plastic responses to pain. p. 301. In Gebhart GF, Hammond OL, Jensen TS (eds): Progress in Pain Research and Management, vol. 2. IASP, Seattle,
1994