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A case of `pure' dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations
Pain 75 (1998) 399–404
Clinical note
A case of ‘pure’ dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations Nadine Attal, Louis Brasseur, Marcel Chauvin, Didier Bouhassira* Unite´ d’Evaluation et de Traitement de la Douleur, Hoˆpital Ambroise Pare´, Boulogne and INSERM U-161, 2 rue d’Ale´sia, 75014 Paris, France Received 28 August 1997; received in revised form 10 December 1997; accepted 11 December 1997
Abstract We report the unusual observation of a patient who presented with the single symptom of a very intense, brush-induced allodynia (dynamic mechanical allodynia) which was strictly confined to the left C2 and C3 dermatomes. All investigations, including a cervical spinal MRI, were initially normal. The clinical picture remained stable for several months until the appearance of spontaneous pain and sensory deficits suggestive of a spinal lesion. A second MRI revealed an intraspinal lesion involving the C2–C5 segments. In accordance with other clinical and animal studies, such an observation of a ‘pure’ dynamic mechano-allodynia suggests that specific mechanisms underlie each component of neuropathic pain. Possible pathophysiological mechanisms are discussed in the light of recent experimental results obtained in animals. 1998 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Neuropathic pain; Central pain; Allodynia; Spinal cord injury
1. Introduction Mechanical allodynia is a frequent symptom in a number of neuropathic and inflammatory pain syndromes. Various animal models have been developed to allow the neurophysiological and pharmacological basis of this symptom to be investigated more appropriately. Several theories have been proposed. However, the neurophysiological mechanisms underlying tactile allodynia continue to be poorly understood (Cervero and Laird, 1996; Willis, 1993). Tactile allodynia is frequently associated with lesions of the spinal cord. Classical authors such as Garcin (1937), Harris (1927), Riddock (1938) and Spiller (1923) emphasized that spontaneous pain was generally associated with various types of ‘over-reaction’ to mechanical or thermal stimuli. These authors also emphasized that pain due to an intraspinal tumour or syringomyelia, might precede other sensory or motor symptoms by many years. Recent studies using quantitative sensory tests in patients with spinal cord * Corresponding author. INSERM U-161, 2 rue d’Ale´sia, 75014 Paris, France. Tel.: +33 1 40789350; fax: +33 1 45881304; e-mail: [email protected]
injuries, have confirmed that evoked pain, including brushinduced allodynia, is frequently associated with spontaneous pain (e.g. Boivie, 1994a,b; Eide et al., 1996). We now report the unusual clinical observation of a woman who presented with a single symptom of very intense, mechanical allodynia confined to the left C2 and C3 dermatomes which could be elicited only by hair deflection or moving light tactile stimuli. This clinical presentation remained stable for several months until the appearance of spontaneous pain and sensory deficits; these symptoms were suggestive of a cervical spinal cord lesion and this was supported by evidence from a MRI. Possible pathophysiological mechanisms are discussed on the basis of recent experimental data obtained in animals.
2. Case report A 68-year-old woman with no history of previous diseases developed a dramatic hypersensitivity of the skin over a period of few weeks. The resulting pain was limited strictly to the left C2 and C3 dermatomes (see Fig. 1). It was provoked selectively by light tactile stimulation of the skin,
0304-3959/98/$19.00 1998 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (98 )0 0007-4
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to such an extent that the patient could not comb her hair or use a pillow and presented with a bare neck and shoulders at every visit. In contrast, the patient did not report any spontaneous pain or dysaesthesia. Her general health was maintained. On initial clinical examination, the only significant finding was the presence of a very intense mechanical allodynia (VAS = 80/100), which was described as a burning and shooting sensation elicited selectively by hair deflection or by lightly stroking the affected skin with a soft brush or cotton wool. Generally, the pain lasted from a few seconds up to 2 min after the end of stimulation. Punctate mechanical stimuli with Von Frey filaments or pressure stimuli applied to a larger area, induced pain only at the onset and end of stimulation (‘on–off’ responses). There was no evidence of allodynia or hyperalgesia to thermal stimuli. Thermal detection and pain thresholds (warm, cold, heat pain and cold pain), measured within both the allodynic area (in the left C3 dermatome) and distal, non-allodynic areas (the left C5 and C7 dermatomes), were similar to those observed on the contralateral, normal, side. Thermal and mechanical sensitivities were normal in the lower limbs. Graphaesthesia, position and vibration senses were normal in all four limbs. The neurological and general examinations were strictly normal in all other respects. Extensive aetiological investigations were performed. They included various laboratory tests, examination of spinal fluid, radiographs of the chest, skull and sinuses, cervical and brain CT-scans and cervical spinal MRI (Fig. 2A). All these examinations were initially normal. The patient received successively and in association with one another, various analgesic treatments. These included tricyclic antidepressants (amitriptyline, up to 125 mg/day), anticonvulsants (carbamazepine, up to 800 mg/day; clonazepam, 4 mg/day), opioids (oral sustained-release morphine, up to 200 mg/day), baclofen (up to 40 mg/day), oral clonidine (up to 0.45 mg/day), topical anaesthetic agents (EMLA), topical capsaicin, superficial cervical blockade, stellate ganglion blocks with local anaesthetics, and systemic local anaesthetics (infusion of xylocaine 300 mg/day followed by oral mexiletine). She did not report significant benefits with any of these treatments except for morphine, which produced a limited attenuation of the allodynia for several weeks, but was associated with sedation. This dynamic mechanical allodynia remained stable and as the single symptom for 14 months. The patient then reported spontaneous pain with a burning quality and dysaesthesia extending bilaterally in the upper limbs (C2–C8 dermatomes). On examination, the triceps tendon reflex was absent on the right side. There was no motor deficit. Brushevoked allodynia was still very severe on the left side (VAS = 80–90/100). Position and vibration senses, and graphaesthesia were normal in the upper and lower limbs. There was no evidence for allodynia or hyperalgesia to thermal stimuli. In contrast, quantitative sensory testing in the C3–C7 dermatomes revealed a significant hypaesthesia
to thermal stimuli and notably to cold, bilaterally. Thermal and mechanical thresholds were not altered in the lower limbs. A second cervical spinal MRI (Fig. 2B) disclosed an intra-spinal lesion at the C2–C5 level. However, further extensive aetiological investigations (laboratory tests, examination of spinal fluid, spinal arteriography) remained negative. The subsequent evolution was unfavorable, with a progressive aggravation of the sensory deficits and the patient then developing pyramidal syndrome in the upper limbs, motor impairment in the lower limbs, ataxia, intermittent confusion and sedation. Finally she died 2 years after the onset of her symptoms. No definitive diagnosis could be achieved since the family refused to allow an autopsy.
3. Conclusion This patient presented with a ‘pure’ brush-induced allodynia which has also been referred to as dynamic mechanical allodynia (Koltzenburg et al., 1992, 1993; Ochoa and Yarnitski, 1993). In this case, the allodynia remained the only symptom for several months before it became related to an intraspinal cervical lesion corresponding with the segmental level of the pain. The clinical and quantitative sensory findings were then comparable to those described previously for syringomyelia (Boivie, 1994b) or for patients
Fig. 1. Distribution of brush-evoked allodynia during the early stages of the disease. The allodynia extended to the left C2 and C3 dermatomes.
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with spinal cord injuries (Beric et al., 1988; Eide et al., 1996). The allodynia and the subsequent spontaneous pain responded poorly to various analgesics as is commonly observed in patients with intraspinal tumours or syringomyelia (Milhorat et al., 1996; Epstein et al., 1993). Unfortunately, the aetiology of the lesion could not be determined with certainty, since an autopsy could not be performed. The gradual onset and late evolution of the disease, together with the radiological aspects of the lesion, could be indicative of an intraspinal tumour. In any case, the initial symptoms observed in this patient suggest an alteration in the central processing of tactile inputs. More specifically, this alteration
Fig. 2. T2-weighted MR images (paramedian sagittal view) of the cervical region. (A) Onset of the disease: normal MRI. The patient complained of pure dynamic mechanical allodynia, without spontaneous pain. (B) Fourteen months later: the spinal canal is widened from C2 to C5. Within the cervical cord, there is an area of increased signal (light area) which extends from C2 to C5 and is bordered by areas of relatively decreased signals (dark areas) representing the spinal cord itself. The lesion was not enhanced by contrast (not shown).
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appeared to involve exclusively the processing of signals mediated by rapidly adapting cutaneous mechanoreceptors and/or hair follicle receptors. Numerous mechanisms have been postulated to account for pain due to spinal cord lesions (for review see Boivie, 1994a; Tasker, 1990; Yezierski, 1996). Most notably, emphasis has been put on an imbalance between sensory information conveyed within the anterolateral quadrant and dorsal columns pathways respectively (Beric et al., 1988). However, such an hypothesis may be more appropriate for spontaneous pain than for allodynia. Recently, Eide et al. (1996) undertook quantitative sensory evaluations of patients with spinal cord injuries who presented with spontaneous pain and various forms of evoked pains. These authors found that mechanical allodynia was not correlated with sensory deficits and concluded that allodynia is not dependent only on lesions of the ventrolateral quadrant or dorsal column pathways, but is likely to involve more specific mechanisms. The fact that our patient presented with a pure mechano-allodynia without sensory deficits or visible lesions in a MRI at the onset of the disease, is in accordance with such a conclusion. On the basis of experimental data from animal models of inflammatory or neuropathic pain, several, not mutually exclusive, neurophysiological mechanisms can be proposed to explain tactile allodynia: (1) a sensitization of mechanical nociceptors; (2) ephaptic or functional cross-talk between large-diameter and small-diameter afferent fibres; (3) a hyperexcitability of nociceptive neurons due to a central sensitization phenomenon; (4) a reorganization of large-diameter fibre terminals in the dorsal horn of the spinal cord, inducing an abnormal activation of nociceptive-specific neurons by non-nociceptive inputs; (5) a deregulation of nociceptive neuronal activity due to a malfunction of segmental and/or descending modulatory systems. Each of these mechanisms will be discussed in the light of the present clinical case. (1) Peripheral nociceptor sensitization (and/or abnormal ectopic impulses) have been observed in some cases of peripheral neuropathy in humans (Cline et al., 1989; Nystrom and Hagbarth, 1981). However, it can reasonably be eliminated in the present case, since there is no experimental evidence to suggest that a central lesion can induce sensitization of peripheral nociceptors. (2) Similarly, ephaptic or functional cross-talk have been demonstrated in nerves or ganglia following peripheral nerve injuries in animals (see Refs. in Devor, 1994), but not after central lesions. (3) Sensitization of spinal nociceptive neurons (i.e., central sensitization) has been demonstrated in animals following inflammation and peripheral neuropathy. It is characterized by a decreased activation threshold, an increase in the size of the excitatory receptive fields, increased spontaneous activity and increased levels of evoked activity in spinal nociceptive neurons (notably convergent neurons). This hyperexcitability of spinal nocicep-
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tive neurons is probably due to functional changes in their electrophysiological properties induced mainly, but not exclusively, by NMDA receptor activation (see Refs. in Dubner, 1991; Price et al., 1994). These pathophysiological models are difficult to apply in the case of central pain since according to the current hypothesis, hyperexcitability of central neurons is dependent on activity in peripheral nociceptive afferents. It has been proposed that various conditions, such as trauma or ischaemia, which result in glutamate liberation in the spinal cord and subsequent activation of NMDA receptors, might induce a state of central sensitization following spinal cord injury (Yezierski, 1996). Such mechanisms might be responsible for spontaneous pain and/or hyperalgesia. However, it is still difficult to explain an isolated dynamic mechano-allodynia on the basis of central sensitization, since there is no experimental evidence suggesting that changes in the excitability of convergent neurons are selective for large diameter fibre inputs. (4) More recently, it has been proposed that mechanical allodynia might be due to structural changes in the central nervous system. This hypothesis is based on anatomical data which have shown novel synaptic contacts between large diameter fibres and dorsal horn neurons in lamina II, after peripheral nerve injury in the rat and the cat (Woolf et al., 1992; Koerber et al., 1994). Such a reorganization could provide an anatomical substrate for mechanical allodynia, since under these pathological conditions, nociceptive-specific neurons located in lamina II might be activated by light tactile stimuli. One could imagine that, in the present clinical case, the initial lesion might have specifically involved a reorganization of large-diameter afferent terminals within the dorsal spinal cord. However, there is no experimental evidence suggesting that central nervous system lesions can induce this type of structural reorganization. (5) The putative role of alterations in segmental modulatory controls is discussed below. Concerning descending controls, the fact that they have a significant role in the modulation of nociception is generally acknowledged. However, there are very few data concerning alterations to these controls during neuropathic pain syndromes due to peripheral or central lesions. Most notably, there are no experimental data suggesting that a dysfunction of descending controls can, segmentally and selectively, alter the responses of nociceptive neurons to mechanical stimuli. Interestingly, however, recent investigations using MRI in patients with syringomyelia associated with pain showed an extension of the syrinx in the dorsolateral quadrant of the spinal cord on the same side and at the appropriate level for the pain (Milhorat et al., 1996). Since the dorsolateral quadrant is considered to be one major pathway for descending controls, it was concluded that pain might be due to a dysfunction of descending modulation. However, it is not known whether in that study, allodynia was associated with the MRI findings and, more importantly, whether patients with syringomyelia, but no pain, also present such a dorsolateral extension of the syrinx.
Alterations of segmental modulatory controls in the spinal cord have been suggested on the basis of electrophysiological experiments in animals with peripheral nerve injury (e.g. Wall and Devor, 1981; Laird and Bennett, 1992). As regards central lesions, the present observation of an isolated dynamic mechanical allodynia is quite reminiscent of results observed in animal models with chronic spinal lesions, induced either photochemically (Hao et al., 1991a; Xu et al., 1992a) or by intraspinal injections of quisqualic acid (an agonist of excitatory amino acid receptors) (Yezierski et al., 1993). Indeed, behavioural and electrophysiological changes suggestive of mechano-allodynia have been observed in these animal models (Hao et al., 1991a,b; Yezierski and Park, 1993). Although these changes were not totally specific for mechanical stimuli and were observed only in animals with significant spinal lesions, these models do seem very interesting from a clinical point of view, since they allow various pharmacological approaches to the problem. It has been shown that, in the ‘photochemical’ model, tactile allodynia can be blocked by NMDA and non-NMDA receptor antagonists, GABAB receptor agonists and CCKB receptor antagonists (see Refs. in Wiesenfeld-Hallin et al., 1994), depending on how long after the lesioning procedure these are employed. Other models of ‘acute’ mechano-allodynia are also very interesting. Intrathecal administration in the rat, of bicuculline (which blocks spinal gabaergic inhibition) or strychnine (which blocks spinal glycinergic inhibition) induces an allodynia which is evoked selectively by light tactile stimuli and hair deflection (Beyer et al., 1985, 1988; Yaksh, 1989; Sherman and Loomis, 1994, 1995). Recent electrophysiological data have indicated that intrathecal application of strychnine selectively increases the responses of spinal convergent neurons to hair movement and light touch. These changes are reversed by the co-administration of NMDA and nonNMDA receptor antagonists (Sorkin and Puig, 1996). These pharmacological and electrophysiological data have led to the proposition that mechanical allodynia might result from a disruption of the presynaptic inhibition of Ab-fibre afferents, normally exerted through GABAergic and/or glycinergic interneurons, which would result in an increased activation of convergent spinal neurons by low-threshold afferents (Wiesenfeld-Hallin et al., 1994; Sherman and Loomis, 1995; Sorkin and Puig, 1996). Although these pathophysiological schemes need to be confirmed, they may provide new pharmacological possibilities for the treatment of this condition. An hypothesis based on a pre-synaptic effect (i.e., increased afferent depolarization and dorsal root reflexes), has recently been proposed to explain experimental tactile allodynia induced by capsaicin injections in humans (Cervero and Laird, 1996). Thus it is possible that different mechanisms may induce similar central dysfunctions. In this respect, it would be important to determine whether such changes in the central nervous system can also be secondary to peripheral nerve injury. Indeed, several lines
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of evidence suggest that, in contrast to static mechanical allodynia, dynamic mechanical allodynia associated with peripheral neuropathy is mediated by large-diameter afferent fibres (see Refs. in Koltzenburg, 1996). This strongly suggests that it depends on specific alterations in the central processing of signals produced by light tactile stimuli. In conclusion, on the basis of the present observation, one can argue strongly against a generalized hyperexcitability of nociceptive neurons to any type of stimuli, as a general pathophysiological explanation for mechano-allodynia. In accordance with recent data obtained in animals, briefly summarized above, one can propose that this symptom is more likely due to selective alterations in the central processing of mechanical inputs at the spinal level. However, other putative mechanisms, such as a reorganization of afferent terminals in the spinal cord or alterations of descending controls, need to be documented in animal models. The similarity of our patient’s symptoms with those observed in several animal models suggests that these models are suitable for the study of the neurophysiological and neuropharmacological mechanisms underlying brush-induced allodynia, which still constitute a challenge for the clinician. More generally, our observations support the idea that each component of neuropathic pains has a specific pathophysiology and might thus benefit from specific treatment. References Beric, A., Dimitrijevic, M.R. and Lindblom, U., Central dysesthesia syndrome in spinal cord injury patients, Pain, 34 (1988) 109–116. Beyer, C., Banas, C., Gomora, P. and Komisaruk, B.R., Prevention of the convulsant and hyperalgesic action of strychnine by intrathecal glycine and related amino acids, Pharmacol. Biochem. Behav., 29 (1988) 73– 78. Beyer, C., Roberts, L.A. and Komisaruk, B.R., Hyperalgesia induced by altered glycinergic activity at the spinal cord, Life Sci., 37 (1985) 875– 882. Boivie, J., Central pain. In: P.D. Wall and R.M. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, Edinburgh, 1994a, pp. 871–902. Boivie, J., Sensory abnormalities in patients with central nervous system lesions as shown by quantitative sensory tests. In: J. Boivie, P. Hansson and U. Lindblom (Eds.), Progress in Pain Research and Management, Vol. 3, IASP Press, Seattle, WA, 1994b, pp. 179–191. Cervero, F. and Laird, J.M.A., Mechanisms of touch-evoked pain (allodynia): a new model, Pain, 68 (1996) 13–23. Cline, M.A., Ochoa, J. and Torebjo¨rk, H.E., Chronic hyperalgesia and skin warming caused by sensitized C nociceptors, Brain, 112 (1989) 621– 647. Devor, M., The pathophysiology of damaged nerve. In: P.D. Wall and R. Melzck (Eds.), Textbook of Pain, Churchill Livingstone, Edinburgh, 1994, pp. 79–100. Dubner, R., Neuronal plasticity and pain following peripheral tissue inflammation or nerve injury. In: M.R. Bond, J.E. Charlton and C.J. Woolf (Eds.), Proceedings of the VIth World Congress on Pain, Elsevier, Amsterdam, 1991, pp. 264–276. Eide, P.K., Jorum, E. and Stenehjetn, A.E., Somatosensory findings in patients with spinal cord injury and central dysaesthesia pain, J. Neurol. Neurosurg. Psychiatry, 60 (1996) 411–415. Epstein, F.J., Farmer, J.P. and Freed, D., Adult intramedullary spinal cord ependymomas: the results of surgery in 38 patients, J. Neurosurg., 79 (1993) 204–209.
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Clinical note
A case of ‘pure’ dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations Nadine Attal, Louis Brasseur, Marcel Chauvin, Didier Bouhassira* Unite´ d’Evaluation et de Traitement de la Douleur, Hoˆpital Ambroise Pare´, Boulogne and INSERM U-161, 2 rue d’Ale´sia, 75014 Paris, France Received 28 August 1997; received in revised form 10 December 1997; accepted 11 December 1997
Abstract We report the unusual observation of a patient who presented with the single symptom of a very intense, brush-induced allodynia (dynamic mechanical allodynia) which was strictly confined to the left C2 and C3 dermatomes. All investigations, including a cervical spinal MRI, were initially normal. The clinical picture remained stable for several months until the appearance of spontaneous pain and sensory deficits suggestive of a spinal lesion. A second MRI revealed an intraspinal lesion involving the C2–C5 segments. In accordance with other clinical and animal studies, such an observation of a ‘pure’ dynamic mechano-allodynia suggests that specific mechanisms underlie each component of neuropathic pain. Possible pathophysiological mechanisms are discussed in the light of recent experimental results obtained in animals. 1998 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Neuropathic pain; Central pain; Allodynia; Spinal cord injury
1. Introduction Mechanical allodynia is a frequent symptom in a number of neuropathic and inflammatory pain syndromes. Various animal models have been developed to allow the neurophysiological and pharmacological basis of this symptom to be investigated more appropriately. Several theories have been proposed. However, the neurophysiological mechanisms underlying tactile allodynia continue to be poorly understood (Cervero and Laird, 1996; Willis, 1993). Tactile allodynia is frequently associated with lesions of the spinal cord. Classical authors such as Garcin (1937), Harris (1927), Riddock (1938) and Spiller (1923) emphasized that spontaneous pain was generally associated with various types of ‘over-reaction’ to mechanical or thermal stimuli. These authors also emphasized that pain due to an intraspinal tumour or syringomyelia, might precede other sensory or motor symptoms by many years. Recent studies using quantitative sensory tests in patients with spinal cord * Corresponding author. INSERM U-161, 2 rue d’Ale´sia, 75014 Paris, France. Tel.: +33 1 40789350; fax: +33 1 45881304; e-mail: [email protected]
injuries, have confirmed that evoked pain, including brushinduced allodynia, is frequently associated with spontaneous pain (e.g. Boivie, 1994a,b; Eide et al., 1996). We now report the unusual clinical observation of a woman who presented with a single symptom of very intense, mechanical allodynia confined to the left C2 and C3 dermatomes which could be elicited only by hair deflection or moving light tactile stimuli. This clinical presentation remained stable for several months until the appearance of spontaneous pain and sensory deficits; these symptoms were suggestive of a cervical spinal cord lesion and this was supported by evidence from a MRI. Possible pathophysiological mechanisms are discussed on the basis of recent experimental data obtained in animals.
2. Case report A 68-year-old woman with no history of previous diseases developed a dramatic hypersensitivity of the skin over a period of few weeks. The resulting pain was limited strictly to the left C2 and C3 dermatomes (see Fig. 1). It was provoked selectively by light tactile stimulation of the skin,
0304-3959/98/$19.00 1998 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (98 )0 0007-4
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to such an extent that the patient could not comb her hair or use a pillow and presented with a bare neck and shoulders at every visit. In contrast, the patient did not report any spontaneous pain or dysaesthesia. Her general health was maintained. On initial clinical examination, the only significant finding was the presence of a very intense mechanical allodynia (VAS = 80/100), which was described as a burning and shooting sensation elicited selectively by hair deflection or by lightly stroking the affected skin with a soft brush or cotton wool. Generally, the pain lasted from a few seconds up to 2 min after the end of stimulation. Punctate mechanical stimuli with Von Frey filaments or pressure stimuli applied to a larger area, induced pain only at the onset and end of stimulation (‘on–off’ responses). There was no evidence of allodynia or hyperalgesia to thermal stimuli. Thermal detection and pain thresholds (warm, cold, heat pain and cold pain), measured within both the allodynic area (in the left C3 dermatome) and distal, non-allodynic areas (the left C5 and C7 dermatomes), were similar to those observed on the contralateral, normal, side. Thermal and mechanical sensitivities were normal in the lower limbs. Graphaesthesia, position and vibration senses were normal in all four limbs. The neurological and general examinations were strictly normal in all other respects. Extensive aetiological investigations were performed. They included various laboratory tests, examination of spinal fluid, radiographs of the chest, skull and sinuses, cervical and brain CT-scans and cervical spinal MRI (Fig. 2A). All these examinations were initially normal. The patient received successively and in association with one another, various analgesic treatments. These included tricyclic antidepressants (amitriptyline, up to 125 mg/day), anticonvulsants (carbamazepine, up to 800 mg/day; clonazepam, 4 mg/day), opioids (oral sustained-release morphine, up to 200 mg/day), baclofen (up to 40 mg/day), oral clonidine (up to 0.45 mg/day), topical anaesthetic agents (EMLA), topical capsaicin, superficial cervical blockade, stellate ganglion blocks with local anaesthetics, and systemic local anaesthetics (infusion of xylocaine 300 mg/day followed by oral mexiletine). She did not report significant benefits with any of these treatments except for morphine, which produced a limited attenuation of the allodynia for several weeks, but was associated with sedation. This dynamic mechanical allodynia remained stable and as the single symptom for 14 months. The patient then reported spontaneous pain with a burning quality and dysaesthesia extending bilaterally in the upper limbs (C2–C8 dermatomes). On examination, the triceps tendon reflex was absent on the right side. There was no motor deficit. Brushevoked allodynia was still very severe on the left side (VAS = 80–90/100). Position and vibration senses, and graphaesthesia were normal in the upper and lower limbs. There was no evidence for allodynia or hyperalgesia to thermal stimuli. In contrast, quantitative sensory testing in the C3–C7 dermatomes revealed a significant hypaesthesia
to thermal stimuli and notably to cold, bilaterally. Thermal and mechanical thresholds were not altered in the lower limbs. A second cervical spinal MRI (Fig. 2B) disclosed an intra-spinal lesion at the C2–C5 level. However, further extensive aetiological investigations (laboratory tests, examination of spinal fluid, spinal arteriography) remained negative. The subsequent evolution was unfavorable, with a progressive aggravation of the sensory deficits and the patient then developing pyramidal syndrome in the upper limbs, motor impairment in the lower limbs, ataxia, intermittent confusion and sedation. Finally she died 2 years after the onset of her symptoms. No definitive diagnosis could be achieved since the family refused to allow an autopsy.
3. Conclusion This patient presented with a ‘pure’ brush-induced allodynia which has also been referred to as dynamic mechanical allodynia (Koltzenburg et al., 1992, 1993; Ochoa and Yarnitski, 1993). In this case, the allodynia remained the only symptom for several months before it became related to an intraspinal cervical lesion corresponding with the segmental level of the pain. The clinical and quantitative sensory findings were then comparable to those described previously for syringomyelia (Boivie, 1994b) or for patients
Fig. 1. Distribution of brush-evoked allodynia during the early stages of the disease. The allodynia extended to the left C2 and C3 dermatomes.
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with spinal cord injuries (Beric et al., 1988; Eide et al., 1996). The allodynia and the subsequent spontaneous pain responded poorly to various analgesics as is commonly observed in patients with intraspinal tumours or syringomyelia (Milhorat et al., 1996; Epstein et al., 1993). Unfortunately, the aetiology of the lesion could not be determined with certainty, since an autopsy could not be performed. The gradual onset and late evolution of the disease, together with the radiological aspects of the lesion, could be indicative of an intraspinal tumour. In any case, the initial symptoms observed in this patient suggest an alteration in the central processing of tactile inputs. More specifically, this alteration
Fig. 2. T2-weighted MR images (paramedian sagittal view) of the cervical region. (A) Onset of the disease: normal MRI. The patient complained of pure dynamic mechanical allodynia, without spontaneous pain. (B) Fourteen months later: the spinal canal is widened from C2 to C5. Within the cervical cord, there is an area of increased signal (light area) which extends from C2 to C5 and is bordered by areas of relatively decreased signals (dark areas) representing the spinal cord itself. The lesion was not enhanced by contrast (not shown).
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appeared to involve exclusively the processing of signals mediated by rapidly adapting cutaneous mechanoreceptors and/or hair follicle receptors. Numerous mechanisms have been postulated to account for pain due to spinal cord lesions (for review see Boivie, 1994a; Tasker, 1990; Yezierski, 1996). Most notably, emphasis has been put on an imbalance between sensory information conveyed within the anterolateral quadrant and dorsal columns pathways respectively (Beric et al., 1988). However, such an hypothesis may be more appropriate for spontaneous pain than for allodynia. Recently, Eide et al. (1996) undertook quantitative sensory evaluations of patients with spinal cord injuries who presented with spontaneous pain and various forms of evoked pains. These authors found that mechanical allodynia was not correlated with sensory deficits and concluded that allodynia is not dependent only on lesions of the ventrolateral quadrant or dorsal column pathways, but is likely to involve more specific mechanisms. The fact that our patient presented with a pure mechano-allodynia without sensory deficits or visible lesions in a MRI at the onset of the disease, is in accordance with such a conclusion. On the basis of experimental data from animal models of inflammatory or neuropathic pain, several, not mutually exclusive, neurophysiological mechanisms can be proposed to explain tactile allodynia: (1) a sensitization of mechanical nociceptors; (2) ephaptic or functional cross-talk between large-diameter and small-diameter afferent fibres; (3) a hyperexcitability of nociceptive neurons due to a central sensitization phenomenon; (4) a reorganization of large-diameter fibre terminals in the dorsal horn of the spinal cord, inducing an abnormal activation of nociceptive-specific neurons by non-nociceptive inputs; (5) a deregulation of nociceptive neuronal activity due to a malfunction of segmental and/or descending modulatory systems. Each of these mechanisms will be discussed in the light of the present clinical case. (1) Peripheral nociceptor sensitization (and/or abnormal ectopic impulses) have been observed in some cases of peripheral neuropathy in humans (Cline et al., 1989; Nystrom and Hagbarth, 1981). However, it can reasonably be eliminated in the present case, since there is no experimental evidence to suggest that a central lesion can induce sensitization of peripheral nociceptors. (2) Similarly, ephaptic or functional cross-talk have been demonstrated in nerves or ganglia following peripheral nerve injuries in animals (see Refs. in Devor, 1994), but not after central lesions. (3) Sensitization of spinal nociceptive neurons (i.e., central sensitization) has been demonstrated in animals following inflammation and peripheral neuropathy. It is characterized by a decreased activation threshold, an increase in the size of the excitatory receptive fields, increased spontaneous activity and increased levels of evoked activity in spinal nociceptive neurons (notably convergent neurons). This hyperexcitability of spinal nocicep-
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tive neurons is probably due to functional changes in their electrophysiological properties induced mainly, but not exclusively, by NMDA receptor activation (see Refs. in Dubner, 1991; Price et al., 1994). These pathophysiological models are difficult to apply in the case of central pain since according to the current hypothesis, hyperexcitability of central neurons is dependent on activity in peripheral nociceptive afferents. It has been proposed that various conditions, such as trauma or ischaemia, which result in glutamate liberation in the spinal cord and subsequent activation of NMDA receptors, might induce a state of central sensitization following spinal cord injury (Yezierski, 1996). Such mechanisms might be responsible for spontaneous pain and/or hyperalgesia. However, it is still difficult to explain an isolated dynamic mechano-allodynia on the basis of central sensitization, since there is no experimental evidence suggesting that changes in the excitability of convergent neurons are selective for large diameter fibre inputs. (4) More recently, it has been proposed that mechanical allodynia might be due to structural changes in the central nervous system. This hypothesis is based on anatomical data which have shown novel synaptic contacts between large diameter fibres and dorsal horn neurons in lamina II, after peripheral nerve injury in the rat and the cat (Woolf et al., 1992; Koerber et al., 1994). Such a reorganization could provide an anatomical substrate for mechanical allodynia, since under these pathological conditions, nociceptive-specific neurons located in lamina II might be activated by light tactile stimuli. One could imagine that, in the present clinical case, the initial lesion might have specifically involved a reorganization of large-diameter afferent terminals within the dorsal spinal cord. However, there is no experimental evidence suggesting that central nervous system lesions can induce this type of structural reorganization. (5) The putative role of alterations in segmental modulatory controls is discussed below. Concerning descending controls, the fact that they have a significant role in the modulation of nociception is generally acknowledged. However, there are very few data concerning alterations to these controls during neuropathic pain syndromes due to peripheral or central lesions. Most notably, there are no experimental data suggesting that a dysfunction of descending controls can, segmentally and selectively, alter the responses of nociceptive neurons to mechanical stimuli. Interestingly, however, recent investigations using MRI in patients with syringomyelia associated with pain showed an extension of the syrinx in the dorsolateral quadrant of the spinal cord on the same side and at the appropriate level for the pain (Milhorat et al., 1996). Since the dorsolateral quadrant is considered to be one major pathway for descending controls, it was concluded that pain might be due to a dysfunction of descending modulation. However, it is not known whether in that study, allodynia was associated with the MRI findings and, more importantly, whether patients with syringomyelia, but no pain, also present such a dorsolateral extension of the syrinx.
Alterations of segmental modulatory controls in the spinal cord have been suggested on the basis of electrophysiological experiments in animals with peripheral nerve injury (e.g. Wall and Devor, 1981; Laird and Bennett, 1992). As regards central lesions, the present observation of an isolated dynamic mechanical allodynia is quite reminiscent of results observed in animal models with chronic spinal lesions, induced either photochemically (Hao et al., 1991a; Xu et al., 1992a) or by intraspinal injections of quisqualic acid (an agonist of excitatory amino acid receptors) (Yezierski et al., 1993). Indeed, behavioural and electrophysiological changes suggestive of mechano-allodynia have been observed in these animal models (Hao et al., 1991a,b; Yezierski and Park, 1993). Although these changes were not totally specific for mechanical stimuli and were observed only in animals with significant spinal lesions, these models do seem very interesting from a clinical point of view, since they allow various pharmacological approaches to the problem. It has been shown that, in the ‘photochemical’ model, tactile allodynia can be blocked by NMDA and non-NMDA receptor antagonists, GABAB receptor agonists and CCKB receptor antagonists (see Refs. in Wiesenfeld-Hallin et al., 1994), depending on how long after the lesioning procedure these are employed. Other models of ‘acute’ mechano-allodynia are also very interesting. Intrathecal administration in the rat, of bicuculline (which blocks spinal gabaergic inhibition) or strychnine (which blocks spinal glycinergic inhibition) induces an allodynia which is evoked selectively by light tactile stimuli and hair deflection (Beyer et al., 1985, 1988; Yaksh, 1989; Sherman and Loomis, 1994, 1995). Recent electrophysiological data have indicated that intrathecal application of strychnine selectively increases the responses of spinal convergent neurons to hair movement and light touch. These changes are reversed by the co-administration of NMDA and nonNMDA receptor antagonists (Sorkin and Puig, 1996). These pharmacological and electrophysiological data have led to the proposition that mechanical allodynia might result from a disruption of the presynaptic inhibition of Ab-fibre afferents, normally exerted through GABAergic and/or glycinergic interneurons, which would result in an increased activation of convergent spinal neurons by low-threshold afferents (Wiesenfeld-Hallin et al., 1994; Sherman and Loomis, 1995; Sorkin and Puig, 1996). Although these pathophysiological schemes need to be confirmed, they may provide new pharmacological possibilities for the treatment of this condition. An hypothesis based on a pre-synaptic effect (i.e., increased afferent depolarization and dorsal root reflexes), has recently been proposed to explain experimental tactile allodynia induced by capsaicin injections in humans (Cervero and Laird, 1996). Thus it is possible that different mechanisms may induce similar central dysfunctions. In this respect, it would be important to determine whether such changes in the central nervous system can also be secondary to peripheral nerve injury. Indeed, several lines
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of evidence suggest that, in contrast to static mechanical allodynia, dynamic mechanical allodynia associated with peripheral neuropathy is mediated by large-diameter afferent fibres (see Refs. in Koltzenburg, 1996). This strongly suggests that it depends on specific alterations in the central processing of signals produced by light tactile stimuli. In conclusion, on the basis of the present observation, one can argue strongly against a generalized hyperexcitability of nociceptive neurons to any type of stimuli, as a general pathophysiological explanation for mechano-allodynia. In accordance with recent data obtained in animals, briefly summarized above, one can propose that this symptom is more likely due to selective alterations in the central processing of mechanical inputs at the spinal level. However, other putative mechanisms, such as a reorganization of afferent terminals in the spinal cord or alterations of descending controls, need to be documented in animal models. The similarity of our patient’s symptoms with those observed in several animal models suggests that these models are suitable for the study of the neurophysiological and neuropharmacological mechanisms underlying brush-induced allodynia, which still constitute a challenge for the clinician. More generally, our observations support the idea that each component of neuropathic pains has a specific pathophysiology and might thus benefit from specific treatment. References Beric, A., Dimitrijevic, M.R. and Lindblom, U., Central dysesthesia syndrome in spinal cord injury patients, Pain, 34 (1988) 109–116. Beyer, C., Banas, C., Gomora, P. and Komisaruk, B.R., Prevention of the convulsant and hyperalgesic action of strychnine by intrathecal glycine and related amino acids, Pharmacol. Biochem. Behav., 29 (1988) 73– 78. Beyer, C., Roberts, L.A. and Komisaruk, B.R., Hyperalgesia induced by altered glycinergic activity at the spinal cord, Life Sci., 37 (1985) 875– 882. Boivie, J., Central pain. In: P.D. Wall and R.M. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, Edinburgh, 1994a, pp. 871–902. Boivie, J., Sensory abnormalities in patients with central nervous system lesions as shown by quantitative sensory tests. In: J. Boivie, P. Hansson and U. Lindblom (Eds.), Progress in Pain Research and Management, Vol. 3, IASP Press, Seattle, WA, 1994b, pp. 179–191. Cervero, F. and Laird, J.M.A., Mechanisms of touch-evoked pain (allodynia): a new model, Pain, 68 (1996) 13–23. Cline, M.A., Ochoa, J. and Torebjo¨rk, H.E., Chronic hyperalgesia and skin warming caused by sensitized C nociceptors, Brain, 112 (1989) 621– 647. Devor, M., The pathophysiology of damaged nerve. In: P.D. Wall and R. Melzck (Eds.), Textbook of Pain, Churchill Livingstone, Edinburgh, 1994, pp. 79–100. Dubner, R., Neuronal plasticity and pain following peripheral tissue inflammation or nerve injury. In: M.R. Bond, J.E. Charlton and C.J. Woolf (Eds.), Proceedings of the VIth World Congress on Pain, Elsevier, Amsterdam, 1991, pp. 264–276. Eide, P.K., Jorum, E. and Stenehjetn, A.E., Somatosensory findings in patients with spinal cord injury and central dysaesthesia pain, J. Neurol. Neurosurg. Psychiatry, 60 (1996) 411–415. Epstein, F.J., Farmer, J.P. and Freed, D., Adult intramedullary spinal cord ependymomas: the results of surgery in 38 patients, J. Neurosurg., 79 (1993) 204–209.
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