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Common characteristics and pathways in neuropathic pain of different etiologies
Drug Discovery Today: Disease Models
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 3, No. 4 2006
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Pain
Common characteristics and pathways in neuropathic pain of different etiologies Kunjumon I. Vadakkan, Hui Xu, Min Zhuo* Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Neuropathic pain results from diverse patho-physiological reasons. Characteristics of this pain are mainly
Section Editor: Min Zhuo – University of Toronto, Toronto, Canada
studied by inducing chronic inflammatory injury of the peripheral nerves in the lower limb. While the etiological differences in neuropathic origin exist at the stage of induction of this pain, some of characteristic features of this pain suggest involvement of central common pathways. Identification of these pathways may assist in discovering novel therapeutic targets for this disease.
Introduction Neuropathic pain results from conditions that can be broadly classified as congenital and acquired arising from local trauma, entrapment, inflammation, infections, IATROGENIC (see Glossary) causes or associated with systemic diseases. It is often characterized by spontaneous burning pain that radiates outside the area of innervation, increased sensitivity to light touch that is perceived as painful (ALLODYNIA) and increased sensitivity to painful stimuli (hyperalgesia). It is refractory to conventional analgesics and often requires a combination drug regime to alleviate the symptoms. A recent review has highlighted the different mechanisms of neuropathic pain disorder [1]. Investigations to study the pathophysiology of this disorder use animal models to evaluate mechanical allodynia and hyperalgesia in response to gene/ protein manipulations and therapeutic agents. Different *Corresponding author: M. Zhuo ([email protected]) 1740-6757/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmod.2006.12.001
animal models of neuropathic pain are widely used [2–13] and some of them were compared [14]. To study the characteristics of neuropathic pain, different animal models have been developed. The present review examines possible etiologies and lists corresponding animal models to examine the possibilities for a common pathophysiology. International association of the study of pain define neuropathic pain as pain initiated or caused by a primary lesion of dysfunction in the nervous system [15]. The spectrum of pain symptoms ranges from spontaneous burning pain at the area of innervation with or without radiation to increased sensitivity to light touch stimuli. Neuropathic pain is long lasting, often does not resolve with time and is usually refractory to conventional treatment. Our understanding of the neuropathic pain mechanism is limited mostly to that arising from nerve ligation in animal models. Therefore, this review focuses on all the etiologies of neuropathic pain, examines existing models for each of them and discusses possibility of a common pathway that can be intervened for therapeutic purposes.
Etiologies of neuropathic pain Neuropathic pain arises from both peripheral and central nervous system causes. A list of etiologies is given below [16]. a. Focal (nerve ligation – injury and entrapment neuropathy). 413
Drug Discovery Today: Disease Models | Pain
Glossary Allodynia: increased sensitivity to light touch stimuli that are perceived as a painful sensation. Hyperpathia: exaggerated pain experience that remains for longer period than the noxious stimulation. Iatrogenic: physician induced Plexus: a combination of adjacent peripheral nerve roots first forming trunks and later emerging as nerves. Plexus results in contribution of more than one nerve root to a single peripheral nerve. While this is advantageous in both sensory and motor functions of the limbs, it may contribute to radiation as well as spread of the pain. Wind up phenomenon: increase in sensitization of pain when painful stimuli are presented repeatedly at short intervals. This is likely owing to the temporal summation that increases the perception of pain.
b. Associated with systemic disorders – collagen disorders (rheumatoid arthritis, systemic lupus erythematosis, diabetes, cancer, HIV/AIDS, metabolic disorders, post-herpetic neuralgia, vascular block of vasa nervosum due to disease and degeneration. c. Congenital (Charcot Mary Tooth disease). d. Inflammatory demyelinating (Guillain Barry syndrome). e. Infections: micobaterium lepri. f. Demyelinating polyneuropathies. g. Vascular lesion of the thalamus. h. Alcohol (vitamin B1 deficiency). i. Vitamin B12 deficiency. j. Heavy metals. k. Injury to the spinal cord. l. Old-age related. m. Iatrogenic: anticancer drugs vincristine, paclitaxel and cis-platin.
Models for neuropathic pain originating from peripheral nerve pathology Out of all the etiologies mentioned above, the one commonly used to raise animal models is that mimic entrapment neuropathy in humans. This is owing to the ease of raising these models in the laboratory. The main principle is to induce chronic pressure over a peripheral nerve segment that will lead to the degeneration of few sensory nerve fibers while leaving other fibers intact. In this review, we will restrict the discussion mostly to sensory fibers and readers may consider possible effects of motor fiber involvement. Pressure effects due to the inflammatory swelling initiated by the ligature, lead to restriction of blood flow in the superficial vessels of the nerve (vasa nervosum). In addition, the compression of nerves results in stimulation of nociceptors in the nervi nervosum [17]. The affected nerve fibers may undergo Wallarian degeneration. The neighboring spared nerve fibers in close contact are thus likely exposed to an altered chemical environment. Together, these changes make the normal nerve fibers acquire impulse generation capabilities. The resulting spontaneous discharges [18] at the site of constric414
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Vol. 3, No. 4 2006
tion may lead to interpreting them as originating from the peripheral afferents. In normal neurons there is retrograde transport of neurotropic factors from the periphery. Nearly half of the nociceptive c-fibers are supported by nerve growth factor [19] and the other half by glia-derived neurotropic factor. The loss of retrograde supply of these factors as a result of the interruption of the nerve ligation, will also lead to alteration in the corresponding dorsal root ganglion (DRG) neuronal nuclei and result in altered expression of neuropeptides, ion channels and receptors and increase their sensitivity and abnormal electrical activity. Even though most of the ligation models of the peripheral nerves were raised to induce pressure effects on sensory fibers, it can also lead to damage to the motor fibers leading to some motor weakness. To overcome this, we have raised a model by ligating the common peroneal nerve at a point where the nerve takes a superficial course close to the skin [9]. However, in separate experiments, ligation of motor fibers also led to neuropathic pain [20] possibly affecting nociceptors in the nervi nervosum supplying those fibers. The presence of fibers from multiple spinal nerve roots in peripheral nerves have important implications in neuropathic pain models raised by ligating them. The lumbar spinal nerves join together to form a lumbosacral PLEXUS (see Glossary) before branching to form peripheral nerves in the lower limb. Within the plexus, the nerve roots from more than one spinal segment fuse to form nerve trunks which in turn remix with the neighboring trunks and finally merge to form peripheral nerves (Fig. 1). The plexus increases contributions from more than one nerve root in a single peripheral nerve and may have advantages in coordinating motor units for the limb movement. Examples of multiple spinal nerve roots are human sciatic nerve [L3, L4, L5, S1 and S2]; human common peroneal nerve (L4, L5, S1 and S2) [21] and rat and mouse sciatic nerves (L3, L4, L5, S1 and S2) [22]. The presence of multiple nerve roots has an important role in mediating spread of synaptic mechanisms of pain at the spinal root level. As discussed earlier, ligation of a single peripheral nerve initiates degenerative changes in its fibers and causes pathological changes in the neighboring fibers at the spinal roots. The presence of nerve fibers from multiple spinal roots elicits neural and synaptic changes in multiple spinal roots and this affects the neighboring nerve fibers.
Models for neuropathic pain resulting from central nervous system pathology These are different types of neuropathic pain that occur in the absence of stimulation of nociceptors at the time of pain sensation. These may be included in two broad categories. 1. Caused by morphological changes in the CNS and is usually associated with trauma or stroke. One typical
Vol. 3, No. 4 2006
Drug Discovery Today: Disease Models | Pain
characterized by an increase in sensitization of pain when painful stimuli are presented repeatedly at short intervals. This change in temporal integration can lead to reduction in pain threshold. It can also lead to expansion of the nociceptive receptive fields in the dorsal horn neurons by involving neighboring synapses [26,27]. Supraspinal areas were also shown to be activated in neuropathic pain by fMRI studies [28]. Different synaptic plastic changes in the anterior cingulate cortex (ACC), one of the cortical regions of the brain involved in the affective component of pain are also reported [29–31]. Even although central mechanisms of peripheral neuropathic pain are being studied, very less models of central pathologies causing neuropathic pain were raised. Specific pathways that lead to neuropathic pain due to many etiological factors are not yet known. Example of this includes anticancer drug-induced neuropathic pain. Figure 1. A cartoon representing sensory fibers in the lower limb peripheral nerves. The individual colors represent different spinal segments. Common peroneal as well as the tibial nerves contain fibers from most of the lumbar spinal segments, indicating that isolated nerve injury of these peripheral nerves can result in spread of painrelated features to other areas of the lower limb. The main difference between the ligation of sciatic nerve and its branches is the number of fibers affected. DRG: dorsal root ganglion. [Note that the motor fibers from the ventral horn join the dorsal root before the formation of the trunks].
example is injury to the thalamus causing thalamic pain (Dejerine-Roussy syndrome) [23]. 2. Caused by central neural plasticity induced by a peripheral source of pain that leads to chronic pain. This central change can take place either at the spinal level or at the supraspinal higher brain areas. Normally, activation of low threshold mechanoreceptors initiating innocuous sensations and high threshold receptors producing nociception relay through separate fiber systems. Pain causes activation of nociceptors and can lead to neural plasticity in the circuits that transmit and process pain signals either in the spinal cord or at the supraspinal levels [23,24]. The net result is a comparatively increased post-synaptic activity for a given input leading to hyperalgesia, HYPERPATHIA (see Glossary) and allodynia (see Glossary). The painful sensation from normally innocuous stimuli is likely due to the abnormal connections between somatosensory tracts and the pain pathway. Destruction of C-fibers by using resiniferatoxin abolished the thermal hyperalgesia but not mechanical allodynia, indicating a possible rewiring of fibers that result in allodynia. Pain processing in the spinal cord is carried out by a complex network of neurons. The interneurons in the dorsal horn receive both inhibitory and excitatory influences from supraspinal processes [25]. Inefficient synapses may change to active ones [26] and may result in re-routing of information and WIND UP PHENOMENON (see Glossary). The latter is
Common central pathways in neuropathic pain of different etiologies Given the multiple etiologies and some of the common features of neuropathic pain, the major question is whether there is a common pathway involved. Lesions of the nervous system can induce plastic changes either at the synapses of the second order of neurons [24] at the spinal cord, third order or higher at the cortical level [32]. Once the expression of neural plasticity sets in at higher centers, it is often associated with more suffering and is more difficult to treat. Phantom pain that can be generated without peripheral stimuli is a typical example [27,33,34]. There are also reports of lateral spread of activation of neurons in the CNS. In these contexts, areas of brain involved in the affective component of pain appear to be a good candidate as a common central pathway in neuropathic pain. Is ACC a common central area involved in neuropathic pain of all origins? Characteristic features in a common central pathway in different etiologies may ultimately result in designing pharmacological agents to alleviate symptoms of neuropathic pain.
Different neuropathic pain models Different types of neuropathic pain models arising from various pathological causes were raised in animals. They differ from each other in the number and types of nerve fibers affected. For some models, the exact mechanism of pathophysiology is not known. Examples include those induced by HIV infection and anticancer drugs. A list of various models of neuropathic pain is given in Table 1. Some of the common pain features in these models may lead to some new possibilities (Box 1).
Model translation to humans Owing to the ethical and technical reasons, the mechanisms of neuropathic pain in humans are not fully clarified using extensive experiments similar to that in animals. However, www.drugdiscoverytoday.com
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Vol. 3, No. 4 2006
Table 1. List of different neuropathic pain models 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Ligation of spinal segmental nerve Loose constrictive ligature around the sciatic nerve Partial ligation of half of the sciatic nerve Partial nerve ligation of the whole sciatic nerve Lesions of sciatic nerve branches Spared nerve injury Ligation of the common peroneal nerve Sciatic inflammatory neuritis Sciatic cryoneurolysis [cold injury] Endoneurial injection of TNF-a Spinal cord injury Injury using excitotoxins Injury by ischemia Spinal cord section Anticancerous drug paclitaxel Spinal cord HIV inflammatory neuropathy
[5] [35] [8] [2] [6] [3] [9] [36] [4] [10] [37] [12] [11] [38] [7] [39]
pathway exists in all the above-mentioned etiologies of neuropathic pain. Plasticity change at the cortical level is a possible common denominator in neuropathic pain of different etiologies. Drug targeting at this level may have useful applications in future.
Acknowledgements We thank the EJLB-Canadian Institutes of Health Research (CIHR), Michael Smith Chair in Neurosciences and Mental Health in Canada and Neuroscience Canada Brain Repair Program for funding to M.Z. K.I.V was supported by the University of Toronto Center for the Study of Pain Clinician Scientist Trainee Fellowship. We thank Long-Jun Wu for commends on the manuscript.
References
Box 1. Outstanding features arising from different models of neuropathic pain Do the molecular mechanisms in different models converge to a common neuronal network? It is not clear whether the molecular mechanisms discovered in neuropathic pain models of nerve injury are common to other types of neuropathic pain, for example in diabetic or HIV neuropathies. A comparative study of the molecular pathways, especially synaptic changes at various levels will facilitate our understanding of different types of neuropathies. Search for a common molecular and/or electrophysiological marker in neuropathic pain may lead to development of pharmacological agents for this disease.
Preventive models for therapeutical targeting Since neuropathic pain often remains resistant to conventional drug regimes, investigations focusing on preventive models of neuropathic pain may be an interim alternative. Blocking initial pathways that trigger the chain of events leading to the central plasticity changes may prevent neuropathic pain development in animal models and this may have applications in humans.
neuropathic pain models arising from different etiologies have been developed in animals with characteristic signs and symptoms. These shows promising evidence that future development of methodologies to reverse the behavioral characteristics in these models may have direct application to humans.
Conclusion Neuropathic pain models created by ligation of peripheral nerves express definite molecular changes at the first order neurons and synapses. However, it is not known whether that induced by paclitaxel or cis-platin can cause neuropathic pain by the same peripheral mechanisms. Considering the nature of the pain and its resistance to conventional inflammatory and analgesic agents, it appears that a common molecular 416
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1 Campbell, J.N. and Meyer, R.A. (2006) Mechanisms of neuropathic pain. Neuron 52, 77–92 2 Malmberg, A.B. and Basbaum, A.I. (1998) Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76, 215–222 3 Decosterd, I. and Woolf, C.J. (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 4 DeLeo, J.A. et al. (1994) Characterization of a neuropathic pain model: sciatic cryoneurolysis in the rat. Pain 56, 9–16 5 Kim, S.H. and Chung, J.M. (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 6 Lee, B.H. et al. (2000) An animal model of neuropathic pain employing injury to the sciatic nerve branches. Neuroreport 11, 657–661 7 Polomano, R.C. et al. (2001) A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 94, 293–304 8 Seltzer, Z. et al. (1990) A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205–218 9 Vadakkan, K.I. et al. (2005) A behavioral model of neuropathic pain induced by ligation of the common peroneal nerve in mice. J. Pain 6, 747–756 10 Wagner, R. and Myers, R.R. (1996) Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7, 2897–2901 11 Xu, X.-J., et al. (2002) Physiological and pharmacological characterization of a rat model of spinal cord injury pain after spinal ischemia. In Spinal Injury Pain: Assessment, Mechanism, Management, Progress in Pain Research and Management (Vol. 23) (Yezierski, R.P. and Burchiel, K.J., eds), pp. 175–187, IASP Press, Seattle. 12 Yezierski, R.P. et al. (1998) Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75, 141–155 13 Zhao, C. et al. (2004) Antiallodynic effects of systemic and intrathecal morphine in the spared nerve injury model of neuropathic pain in rats. Anesthesiology 100, 905–911 14 Dowdall, T. et al. (2005) Comparison of five different rat models of peripheral nerve injury. Pharmacol. Biochem. Behav. 80, 93–108 15 Merskey, H. and Bogduck, N. (1994) Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms (2nd edn), IASP Press, Seattle 16 Bromberg, M.B. and A.G. Smith. (2006) Handbook of Peripheral Neuropathy. Taylor and Francis Edn. Neurological Disease and Therapy series, pp. 1–17; ISBN:9780824754327 17 Sugar, O. et al. (1990) Nerve stretching and the nerve nervosum. Surg. Neurol. 184–187 18 Wall, P.D. et al. (1979) Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7, 103–111
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Bennett, A.D. et al. (1999) NGF levels decrease in the spinal cord and dorsal root ganglion after spinal hemisection. Neuroreport 10, 889–893 Li, Y. et al. (2000) Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain 85, 493–502 Olson, T.R. (1996) Animated Dissection of Anatomy for Medicine. Williams and Wilkins 220 Greene, E.C. (1955) Anatomy of the Rat. Hafner publishing company, New York Craig, A.D. et al. (1994) A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773 Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769 Zhuo, M. and Gebhart, G.F. (1997) Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. J. Neurophysiol. 78, 746–758 Li, P. and Zhuo, M. (1998) Silent glutamatergic synapases and nociception in mammalian spinal cord. Nature 393, 695–698 Hong, C.Z. and Simons, D.G. (1998) Pathophysiologic and electrophysiologic mechanisms of myofascial trigger points. Arch. Phys. Med. Rehabil. 79, 863–872 Maihofner, C. et al. (2006) Functional imaging of allodynia in complex regional pain syndrome. Neurology 66, 711–717 Wei, F. et al. (1999) Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J. Neurosci. 19, 9346–9354
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Wei, F. and Zhuo, M. (2001) Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetized rat. J. Physiol. 532, 823–833 Zhao, M.G. et al. (2006) Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain. J. Neurosci. 26, 8923–8930 Zhuo, M. (2004) Central plasticity in pathological pain. Novartis Found Symp. 261, 132–145 discussion 145–154 Jastreboff, P.J. (1990) Phantom auditory perception [tinnitus]: mechanisms of generation and perception. Neurosci. Res. 8, 221–254 Melzack, R. (1992) Phantom limb pain. Patol. Fiziol. Eksp. Ter. 52–54 Bennett, G.J. and Xie, Y.K. (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 Chacur, M. et al. (2001) A new model of sciatic inflammatory neuritis: induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain 94, 231–244 Burchiel, K.J. and Burns, A.S. (2001) Summary statement: pain, spasticity, and bladder and sexual function after spinal cord injury. Spine 26, S161 Sung, B. et al. (1998) Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats. Neurosci. Lett. 246, 117–119 Milligan, E.D. et al. (2001) Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J. Neurosci. 21, 2808–2819
www.drugdiscoverytoday.com
417
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 3, No. 4 2006
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Pain
Common characteristics and pathways in neuropathic pain of different etiologies Kunjumon I. Vadakkan, Hui Xu, Min Zhuo* Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Neuropathic pain results from diverse patho-physiological reasons. Characteristics of this pain are mainly
Section Editor: Min Zhuo – University of Toronto, Toronto, Canada
studied by inducing chronic inflammatory injury of the peripheral nerves in the lower limb. While the etiological differences in neuropathic origin exist at the stage of induction of this pain, some of characteristic features of this pain suggest involvement of central common pathways. Identification of these pathways may assist in discovering novel therapeutic targets for this disease.
Introduction Neuropathic pain results from conditions that can be broadly classified as congenital and acquired arising from local trauma, entrapment, inflammation, infections, IATROGENIC (see Glossary) causes or associated with systemic diseases. It is often characterized by spontaneous burning pain that radiates outside the area of innervation, increased sensitivity to light touch that is perceived as painful (ALLODYNIA) and increased sensitivity to painful stimuli (hyperalgesia). It is refractory to conventional analgesics and often requires a combination drug regime to alleviate the symptoms. A recent review has highlighted the different mechanisms of neuropathic pain disorder [1]. Investigations to study the pathophysiology of this disorder use animal models to evaluate mechanical allodynia and hyperalgesia in response to gene/ protein manipulations and therapeutic agents. Different *Corresponding author: M. Zhuo ([email protected]) 1740-6757/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmod.2006.12.001
animal models of neuropathic pain are widely used [2–13] and some of them were compared [14]. To study the characteristics of neuropathic pain, different animal models have been developed. The present review examines possible etiologies and lists corresponding animal models to examine the possibilities for a common pathophysiology. International association of the study of pain define neuropathic pain as pain initiated or caused by a primary lesion of dysfunction in the nervous system [15]. The spectrum of pain symptoms ranges from spontaneous burning pain at the area of innervation with or without radiation to increased sensitivity to light touch stimuli. Neuropathic pain is long lasting, often does not resolve with time and is usually refractory to conventional treatment. Our understanding of the neuropathic pain mechanism is limited mostly to that arising from nerve ligation in animal models. Therefore, this review focuses on all the etiologies of neuropathic pain, examines existing models for each of them and discusses possibility of a common pathway that can be intervened for therapeutic purposes.
Etiologies of neuropathic pain Neuropathic pain arises from both peripheral and central nervous system causes. A list of etiologies is given below [16]. a. Focal (nerve ligation – injury and entrapment neuropathy). 413
Drug Discovery Today: Disease Models | Pain
Glossary Allodynia: increased sensitivity to light touch stimuli that are perceived as a painful sensation. Hyperpathia: exaggerated pain experience that remains for longer period than the noxious stimulation. Iatrogenic: physician induced Plexus: a combination of adjacent peripheral nerve roots first forming trunks and later emerging as nerves. Plexus results in contribution of more than one nerve root to a single peripheral nerve. While this is advantageous in both sensory and motor functions of the limbs, it may contribute to radiation as well as spread of the pain. Wind up phenomenon: increase in sensitization of pain when painful stimuli are presented repeatedly at short intervals. This is likely owing to the temporal summation that increases the perception of pain.
b. Associated with systemic disorders – collagen disorders (rheumatoid arthritis, systemic lupus erythematosis, diabetes, cancer, HIV/AIDS, metabolic disorders, post-herpetic neuralgia, vascular block of vasa nervosum due to disease and degeneration. c. Congenital (Charcot Mary Tooth disease). d. Inflammatory demyelinating (Guillain Barry syndrome). e. Infections: micobaterium lepri. f. Demyelinating polyneuropathies. g. Vascular lesion of the thalamus. h. Alcohol (vitamin B1 deficiency). i. Vitamin B12 deficiency. j. Heavy metals. k. Injury to the spinal cord. l. Old-age related. m. Iatrogenic: anticancer drugs vincristine, paclitaxel and cis-platin.
Models for neuropathic pain originating from peripheral nerve pathology Out of all the etiologies mentioned above, the one commonly used to raise animal models is that mimic entrapment neuropathy in humans. This is owing to the ease of raising these models in the laboratory. The main principle is to induce chronic pressure over a peripheral nerve segment that will lead to the degeneration of few sensory nerve fibers while leaving other fibers intact. In this review, we will restrict the discussion mostly to sensory fibers and readers may consider possible effects of motor fiber involvement. Pressure effects due to the inflammatory swelling initiated by the ligature, lead to restriction of blood flow in the superficial vessels of the nerve (vasa nervosum). In addition, the compression of nerves results in stimulation of nociceptors in the nervi nervosum [17]. The affected nerve fibers may undergo Wallarian degeneration. The neighboring spared nerve fibers in close contact are thus likely exposed to an altered chemical environment. Together, these changes make the normal nerve fibers acquire impulse generation capabilities. The resulting spontaneous discharges [18] at the site of constric414
www.drugdiscoverytoday.com
Vol. 3, No. 4 2006
tion may lead to interpreting them as originating from the peripheral afferents. In normal neurons there is retrograde transport of neurotropic factors from the periphery. Nearly half of the nociceptive c-fibers are supported by nerve growth factor [19] and the other half by glia-derived neurotropic factor. The loss of retrograde supply of these factors as a result of the interruption of the nerve ligation, will also lead to alteration in the corresponding dorsal root ganglion (DRG) neuronal nuclei and result in altered expression of neuropeptides, ion channels and receptors and increase their sensitivity and abnormal electrical activity. Even though most of the ligation models of the peripheral nerves were raised to induce pressure effects on sensory fibers, it can also lead to damage to the motor fibers leading to some motor weakness. To overcome this, we have raised a model by ligating the common peroneal nerve at a point where the nerve takes a superficial course close to the skin [9]. However, in separate experiments, ligation of motor fibers also led to neuropathic pain [20] possibly affecting nociceptors in the nervi nervosum supplying those fibers. The presence of fibers from multiple spinal nerve roots in peripheral nerves have important implications in neuropathic pain models raised by ligating them. The lumbar spinal nerves join together to form a lumbosacral PLEXUS (see Glossary) before branching to form peripheral nerves in the lower limb. Within the plexus, the nerve roots from more than one spinal segment fuse to form nerve trunks which in turn remix with the neighboring trunks and finally merge to form peripheral nerves (Fig. 1). The plexus increases contributions from more than one nerve root in a single peripheral nerve and may have advantages in coordinating motor units for the limb movement. Examples of multiple spinal nerve roots are human sciatic nerve [L3, L4, L5, S1 and S2]; human common peroneal nerve (L4, L5, S1 and S2) [21] and rat and mouse sciatic nerves (L3, L4, L5, S1 and S2) [22]. The presence of multiple nerve roots has an important role in mediating spread of synaptic mechanisms of pain at the spinal root level. As discussed earlier, ligation of a single peripheral nerve initiates degenerative changes in its fibers and causes pathological changes in the neighboring fibers at the spinal roots. The presence of nerve fibers from multiple spinal roots elicits neural and synaptic changes in multiple spinal roots and this affects the neighboring nerve fibers.
Models for neuropathic pain resulting from central nervous system pathology These are different types of neuropathic pain that occur in the absence of stimulation of nociceptors at the time of pain sensation. These may be included in two broad categories. 1. Caused by morphological changes in the CNS and is usually associated with trauma or stroke. One typical
Vol. 3, No. 4 2006
Drug Discovery Today: Disease Models | Pain
characterized by an increase in sensitization of pain when painful stimuli are presented repeatedly at short intervals. This change in temporal integration can lead to reduction in pain threshold. It can also lead to expansion of the nociceptive receptive fields in the dorsal horn neurons by involving neighboring synapses [26,27]. Supraspinal areas were also shown to be activated in neuropathic pain by fMRI studies [28]. Different synaptic plastic changes in the anterior cingulate cortex (ACC), one of the cortical regions of the brain involved in the affective component of pain are also reported [29–31]. Even although central mechanisms of peripheral neuropathic pain are being studied, very less models of central pathologies causing neuropathic pain were raised. Specific pathways that lead to neuropathic pain due to many etiological factors are not yet known. Example of this includes anticancer drug-induced neuropathic pain. Figure 1. A cartoon representing sensory fibers in the lower limb peripheral nerves. The individual colors represent different spinal segments. Common peroneal as well as the tibial nerves contain fibers from most of the lumbar spinal segments, indicating that isolated nerve injury of these peripheral nerves can result in spread of painrelated features to other areas of the lower limb. The main difference between the ligation of sciatic nerve and its branches is the number of fibers affected. DRG: dorsal root ganglion. [Note that the motor fibers from the ventral horn join the dorsal root before the formation of the trunks].
example is injury to the thalamus causing thalamic pain (Dejerine-Roussy syndrome) [23]. 2. Caused by central neural plasticity induced by a peripheral source of pain that leads to chronic pain. This central change can take place either at the spinal level or at the supraspinal higher brain areas. Normally, activation of low threshold mechanoreceptors initiating innocuous sensations and high threshold receptors producing nociception relay through separate fiber systems. Pain causes activation of nociceptors and can lead to neural plasticity in the circuits that transmit and process pain signals either in the spinal cord or at the supraspinal levels [23,24]. The net result is a comparatively increased post-synaptic activity for a given input leading to hyperalgesia, HYPERPATHIA (see Glossary) and allodynia (see Glossary). The painful sensation from normally innocuous stimuli is likely due to the abnormal connections between somatosensory tracts and the pain pathway. Destruction of C-fibers by using resiniferatoxin abolished the thermal hyperalgesia but not mechanical allodynia, indicating a possible rewiring of fibers that result in allodynia. Pain processing in the spinal cord is carried out by a complex network of neurons. The interneurons in the dorsal horn receive both inhibitory and excitatory influences from supraspinal processes [25]. Inefficient synapses may change to active ones [26] and may result in re-routing of information and WIND UP PHENOMENON (see Glossary). The latter is
Common central pathways in neuropathic pain of different etiologies Given the multiple etiologies and some of the common features of neuropathic pain, the major question is whether there is a common pathway involved. Lesions of the nervous system can induce plastic changes either at the synapses of the second order of neurons [24] at the spinal cord, third order or higher at the cortical level [32]. Once the expression of neural plasticity sets in at higher centers, it is often associated with more suffering and is more difficult to treat. Phantom pain that can be generated without peripheral stimuli is a typical example [27,33,34]. There are also reports of lateral spread of activation of neurons in the CNS. In these contexts, areas of brain involved in the affective component of pain appear to be a good candidate as a common central pathway in neuropathic pain. Is ACC a common central area involved in neuropathic pain of all origins? Characteristic features in a common central pathway in different etiologies may ultimately result in designing pharmacological agents to alleviate symptoms of neuropathic pain.
Different neuropathic pain models Different types of neuropathic pain models arising from various pathological causes were raised in animals. They differ from each other in the number and types of nerve fibers affected. For some models, the exact mechanism of pathophysiology is not known. Examples include those induced by HIV infection and anticancer drugs. A list of various models of neuropathic pain is given in Table 1. Some of the common pain features in these models may lead to some new possibilities (Box 1).
Model translation to humans Owing to the ethical and technical reasons, the mechanisms of neuropathic pain in humans are not fully clarified using extensive experiments similar to that in animals. However, www.drugdiscoverytoday.com
415
Drug Discovery Today: Disease Models | Pain
Vol. 3, No. 4 2006
Table 1. List of different neuropathic pain models 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Ligation of spinal segmental nerve Loose constrictive ligature around the sciatic nerve Partial ligation of half of the sciatic nerve Partial nerve ligation of the whole sciatic nerve Lesions of sciatic nerve branches Spared nerve injury Ligation of the common peroneal nerve Sciatic inflammatory neuritis Sciatic cryoneurolysis [cold injury] Endoneurial injection of TNF-a Spinal cord injury Injury using excitotoxins Injury by ischemia Spinal cord section Anticancerous drug paclitaxel Spinal cord HIV inflammatory neuropathy
[5] [35] [8] [2] [6] [3] [9] [36] [4] [10] [37] [12] [11] [38] [7] [39]
pathway exists in all the above-mentioned etiologies of neuropathic pain. Plasticity change at the cortical level is a possible common denominator in neuropathic pain of different etiologies. Drug targeting at this level may have useful applications in future.
Acknowledgements We thank the EJLB-Canadian Institutes of Health Research (CIHR), Michael Smith Chair in Neurosciences and Mental Health in Canada and Neuroscience Canada Brain Repair Program for funding to M.Z. K.I.V was supported by the University of Toronto Center for the Study of Pain Clinician Scientist Trainee Fellowship. We thank Long-Jun Wu for commends on the manuscript.
References
Box 1. Outstanding features arising from different models of neuropathic pain Do the molecular mechanisms in different models converge to a common neuronal network? It is not clear whether the molecular mechanisms discovered in neuropathic pain models of nerve injury are common to other types of neuropathic pain, for example in diabetic or HIV neuropathies. A comparative study of the molecular pathways, especially synaptic changes at various levels will facilitate our understanding of different types of neuropathies. Search for a common molecular and/or electrophysiological marker in neuropathic pain may lead to development of pharmacological agents for this disease.
Preventive models for therapeutical targeting Since neuropathic pain often remains resistant to conventional drug regimes, investigations focusing on preventive models of neuropathic pain may be an interim alternative. Blocking initial pathways that trigger the chain of events leading to the central plasticity changes may prevent neuropathic pain development in animal models and this may have applications in humans.
neuropathic pain models arising from different etiologies have been developed in animals with characteristic signs and symptoms. These shows promising evidence that future development of methodologies to reverse the behavioral characteristics in these models may have direct application to humans.
Conclusion Neuropathic pain models created by ligation of peripheral nerves express definite molecular changes at the first order neurons and synapses. However, it is not known whether that induced by paclitaxel or cis-platin can cause neuropathic pain by the same peripheral mechanisms. Considering the nature of the pain and its resistance to conventional inflammatory and analgesic agents, it appears that a common molecular 416
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