Spinal Cord Injuries Containing Asymmetrical Damage in the Ventrolateral Funiculus Is Associated With a Higher Incidence of At-Level Allodynia


      Approximately 70% of male rats receiving severe T8 spinal contusions develop allodynia in T5-7 dermatomes (at-level) beginning 2 weeks after injury. In contrast, rats having either complete transections or dorsal hemisections do not develop allodynia at-level after chronic spinal cord injury (SCI). In the present study, incomplete laceration and contusion injuries were made to test for neuroanatomical correlates between areas of white matter damage/sparing at the lesion epicenter and the presence/absence of allodynia. After incomplete laceration lesions and 6 weeks of behavioral testing, histological reconstruction and analysis of the lesion epicenters revealed a significant difference (P < .001) in the amount of ventrolateral funiculus (VLF) asymmetry between rats showing pain-like responses evoked by touch (74.5% ± 8.4% side-to-side difference in VLF damage) versus those not responding to touch (11.3% ± 4.4% side-to-side difference in VLF damage). A 5-week mean allodynia score for each rat that incorporates a full range of forces that are all innocuous in intact controls revealed that the degree of hypersensitivity at level is related to the extent of VLF asymmetry after SCI. No other damaged spinal white matter or gray matter area was correlated with sensitivity to touch. Similar findings were obtained for rats receiving T8 contusions, a more clinically relevant injury. These data suggest that different extents of damage/sparing between the 2 sides of VLF probably are a requisite for the development of allodynia after SCI.


      A side-to-side lesion asymmetry after chronic SCI in a rodent model was found to be highly correlated with the presence and degree of allodynia. Greater insight of key factors contributing to the development and maintenance of chronic neuropathic pain is important for improving quality of life.

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        • Abraham K.E.
        • McGinty J.F.
        • Brewer K.L.
        Spinal and supraspinal changes in opioid mRNA expression are related to the onset of pain behaviors following excitotoxic spinal cord injury.
        Pain. 2001; 90: 181-190
        • Berkley K.J.
        • Hubscher C.H.
        Are there separate central nervous system pathways for touch and pain?.
        Nat Med. 1995; 1: 766-773
        • Boivie J.
        Hyperalgesia and allodynia in patients with CNS lesions.
        in: Willis Jr, W.D. Hyperalgesia and Allodynia. Raven Press, Ltd, New York1992: 363-373
        • Campbell J.N.
        • Meyer R.A.
        Mechanisms of neuropathic pain.
        Neuron. 2006; 52: 77-92
        • Carson F.
        Histotechnology: A Self-Instructional Text.
        American Society of Clinical Pathologists, Chicago1990
        • Christensen M.D.
        • Everhart A.W.
        • Pickelman J.T.
        • Hulsebosch C.E.
        Mechanical and thermal allodynia in chronic central pain following spinal cord injury.
        Pain. 1996; 68: 97-107
        • Christensen M.D.
        • Hulsebosch C.E.
        Chronic central pain after spinal cord injury.
        J Neurotrauma. 1997; 14: 517-537
        • Cliffer K.D.
        • Burstein R.
        • Giesler Jr., G.J.
        Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats.
        J Neurosci. 1991; 11: 852-868
        • Crown E.D.
        • Ye Z.
        • Johnson K.M.
        • Xu G.Y.
        • McAdoo D.J.
        • Hulsebosch C.E.
        Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury.
        Exp Neurol. 2006; 199: 397-407
        • Davidoff G.
        • Roth E.J.
        Clinical characteristics of central (dysesthetic) pain in spinal cord injury patients.
        in: Casey K.L. Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York1991: 77-83
        • Donovan W.H.
        • Dimitrijevic M.R.
        • Dahm L.
        • Dimitrijevic M.
        Neurophysiological approaches to chronic pain following spinal cord injury.
        Paraplegia. 1982; 20: 135-146
        • Eaton M.J.
        Cell and molecular approaches to the attenuation of pain after spinal cord injury.
        J Neurotrauma. 2006; 23: 549-559
        • Finnerup N.B.
        • Gyldensted C.
        • Nielsen E.
        • Kristensen A.D.
        • Bach F.W.
        • Jensen T.S.
        MRI in chronic spinal cord injury patients with and without central pain.
        Neurology. 2003; 61: 1569-1575
        • Finnerup N.B.
        • Sorensen L.
        • Biering-Sorensen F.
        • Johannesen I.L.
        • Jensen T.S.
        Segmental hypersensitivity and spinothalamic function in spinal cord injury pain.
        Exp Neurol. 2007; 207: 139-149
        • Garcia R.
        • Tocco G.
        • Baudry M.
        • Thompson R.F.
        Exposure to a conditioned aversive environment interferes with long-term potentiation induction in the fimbria-CA3 pathway.
        Neuroscience. 1998; 82: 139-145
        • Gerke M.B.
        • Duggan A.W.
        • Xu L.
        • Siddall P.J.
        Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury.
        Neuroscience. 2003; 117: 715-722
        • Hains B.C.
        • Klein J.P.
        • Saab C.Y.
        • Craner M.J.
        • Black J.A.
        • Waxman S.G.
        Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury.
        J Neurosci. 2003; 23: 8881-8892
      1. Hatem SM, Attal NM, Gautron M, Parker F, Plaghki L, Bouhassira D: Pathophysiology of central neuropathic pain: Psychophysical and electrophysiological correlates in patients with syringomyelia. Program No. 185.16. 2007 Neuroscience Meeting Planner. San Diego, CA, Society for Neuroscience, 2007. Online. Available at: Accessed February 1, 2010

        • Hosobuchi Y.
        Subcortical electrical stimulation for control of intractable pain in humans: Report of 122 cases (1970-1984).
        J Neurosurg. 1986; 64: 543-553
        • Hubbard D.T.
        • Nakashima B.R.
        • Lee I.
        • Takahashi L.K.
        Activation of basolateral amygdala corticotropin-releasing factor 1 receptors modulates the consolidation of contextual fear.
        Neuroscience. 2007; 150: 818-828
        • Hubscher C.H.
        • Johnson R.D.
        Changes in neuronal receptive field characteristics in caudal brain stem following chronic spinal cord injury.
        J Neurotrauma. 1999; 16: 533-541
        • Hubscher C.H.
        • Johnson R.D.
        Differential effects of chronic spinal hemisection on somatic and visceral inputs to caudal brainstem.
        Brain Res. 2002; 947: 234-242
        • Hubscher C.H.
        • Johnson R.D.
        Responses of thalamic neurons to input from the male genitalia.
        J Neurophysiol. 2003; 89: 2-11
        • Hubscher C.H.
        • Johnson R.D.
        Chronic spinal cord injury induced changes in the responses of thalamic neurons.
        Exp Neurol. 2006; 197: 177-188
        • Hubscher C.H.
        • Kaddumi E.G.
        • Johnson R.D.
        Segmental neuropathic pain does not develop in male rats with complete spinal transections.
        J Neurotrauma. 2008; 25: 1241-1245
        • Hubscher C.H.
        • Petruska J.C.
        • Rau K.K.
        • Johnson R.D.
        Co-expression of P2X receptor subunits on rat nodose neurons that bind the isolectin GS-I-B4.
        Neuroreport. 2001; 12: 2995-2997
        • Hugues S.
        • Kessal K.
        • Hunt M.J.
        • Garcia R.
        A conditioned stressful environment causes short-term metaplastic-like changes in the rat nucleus accumbens.
        J Neurophysiol. 2003; 90: 3224-3231
        • Hulsebosch C.E.
        • Hains B.C.
        • Crown E.D.
        • Carlton S.M.
        Mechanisms of chronic central neuropathic pain after spinal cord injury.
        Brain Res Rev. 2009; 60: 202-213
        • Hulsebosch C.E.
        • Xu G.Y.
        • Perez-Polo J.R.
        • Westlund K.N.
        • Taylor C.P.
        • McAdoo D.J.
        Rodent model of chronic central pain after spinal cord contusion injury and effects of gabapentin.
        J Neurotrauma. 2000; 17: 1205-1217
        • Keirstead H.S.
        • Nistor G.
        • Bernal G.
        • Totoiu M.
        • Cloutier F.
        • Sharp K.
        • Steward O.
        Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.
        J Neurosci. 2005; 25: 4694-4705
        • Keizer D.
        • van Wijhe M.
        • Post W.J.
        • Uges D.R.
        • Wierda J.M.
        Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain: A pilot study.
        Eur J Anaesthesiol. 2007; 24: 658-663
        • Keizer D.
        • van Wijhe M.
        • Post W.J.
        • Wierda J.M.
        Quantifying allodynia in patients suffering from unilateral neuropathic pain using von Frey monofilaments.
        Clin J Pain. 2007; 23: 85-90
        • Kloos A.D.
        • Fisher L.C.
        • Detloff M.R.
        • Hassenzahl D.L.
        • Basso D.M.
        Stepwise motor and all-or-none sensory recovery is associated with nonlinear sparing after incremental spinal cord injury in rats.
        Exp Neurol. 2005; 191: 251-265
        • Kohno T.
        • Ji R.R.
        • Ito N.
        • Allchorne A.J.
        • Befort K.
        • Karchewski L.A.
        • Woolf C.J.
        Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord.
        Pain. 2005; 117: 77-87
        • Lenz F.A.
        • Kwan H.C.
        • Martin R.
        • Tasker R.
        • Richardson R.T.
        • Dostrovsky J.O.
        Characteristics of somatotopic organization and spontaneous neuronal activity in the region of the thalamic principal sensory nucleus in patients with spinal cord transection.
        J Neurophysiol. 1994; 72: 1570-1587
        • Luna L.
        Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology.
        McGraw Hill, New York1968
        • Markenson J.A.
        Mechanisms of chronic pain.
        Am J Med. 1996; 101: 6S-18S
        • Melzack R.
        • Wall P.D.
        • Ty T.C.
        Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries.
        Pain. 1982; 14: 33-43
      2. Merskey H, Bogduk N: Classification of Chronic Pain. IASP Press, Seattle, 1994

        • Moore K.A.
        • Kohno T.
        • Karchewski L.A.
        • Scholz J.
        • Baba H.
        • Woolf C.J.
        Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.
        J Neurosci. 2002; 22: 6724-6731
        • Niv D.
        • Devor M.
        Refractory neuropathic pain: The nature and extent of the problem.
        Pain Pract. 2006; 6: 3-9
        • Oatway M.A.
        • Chen Y.
        • Weaver L.C.
        The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury.
        Pain. 2004; 110: 259-268
        • Pattany P.M.
        • Yezierski R.P.
        • Widerstrom-Noga E.G.
        • Bowen B.C.
        • Martinez-Arizala A.
        • Garcia B.R.
        • Quencer R.M.
        Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury.
        AJNR Am J Neuroradiol. 2002; 23: 901-905
        • Porreca F.
        • Burgess S.E.
        • Gardell L.R.
        • Vanderah T.W.
        • Malan Jr., T.P.
        • Ossipov M.H.
        • Lappi D.A.
        • Lai J.
        Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor.
        J Neurosci. 2001; 21: 5281-5288
        • Reed W.R.
        • Chadha H.K.
        • Hubscher C.H.
        Effects of 17β-estradiol on responses of viscerosomatic convergent thalamic neurons in the ovariectomized female rat.
        J Neurophysiol. 2009; 102: 1062-1074
        • Richardson R.R.
        • Meyer P.R.
        • Cerullo L.J.
        Neurostimulation in the modulation of intractable paraplegic and traumatic neuroma pains.
        Pain. 1980; 8: 75-84
        • Saade N.E.
        • Al Amin H.
        • Abdel Baki S.
        • Safieh-Garabedian B.
        • Atweh S.F.
        Jabbur SJ: Transient attenuation of neuropathic manifestations in rats following lesion or reversible block of the lateral thalamic somatosensory nuclei.
        Exp Neurol. 2006; 197: 157-166
        • Scheff S.W.
        • Rabchevsky A.G.
        • Fugaccia I.
        • Main J.A.
        • Lumpp Jr., J.E.
        Experimental modeling of spinal cord injury: characterization of a force-defined injury device.
        J Neurotrauma. 2003; 20: 179-193
        • Siddall P.
        • Xu C.L.
        • Cousins M.
        Allodynia following traumatic spinal cord injury in the rat.
        Neuroreport. 1995; 6: 1241-1244
        • Siddall P.J.
        • Loeser J.D.
        Pain following spinal cord injury.
        Spinal Cord. 2001; 39: 63-73
        • Spennato G.
        • Zerbib C.
        • Mondadori C.
        • Garcia R.
        Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation.
        Psychopharmacology (Berl). 2008; 196: 583-589
        • Sun H.
        • Ren K.
        • Zhong C.M.
        • Ossipov M.H.
        • Malan T.P.
        • Lai J.
        • Porreca F.
        Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections.
        Pain. 2001; 90: 105-111
        • Sved P.
        • Siddall P.J.
        • McClelland J.
        • Cousins M.J.
        Relationship between surgery and pain following spinal cord injury.
        Spinal Cord. 1997; 35: 526-530
        • Villanueva L.
        • Nathan P.W.
        Multiple pain pathways.
        in: Devor M. Rowbotham M.C. Wiesenfeld-Hallin Z. Proceedings of the 9th World Congress on Pain. IASP Press, Seattle2000: 371-386
        • Wang G.
        • Thompson S.M.
        Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: Thalamic hyperexcitability after spinothalamic tract lesions.
        J Neurosci. 2008; 28: 11959-11969
        • Wasner G.
        • Lee B.B.
        • Engel S.
        • McLachlan E.
        Residual spinothalamic tract pathways predict development of central pain after spinal cord injury.
        Brain. 2008; 131: 2387-2400
        • Woolf C.J.
        Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat.
        Pain. 1984; 18: 325-343
        • Woolf C.J.
        • Swett J.E.
        The cutaneous contribution to the hamstring flexor reflex in the rat: An electrophysiological and anatomical study.
        Brain Res. 1984; 303: 299-312
        • Yaksh T.L.
        Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: Effects of modulatory receptor systems and excitatory amino acid antagonists.
        Pain. 1989; 37: 111-123
        • Yezierski R.P.
        • Liu S.
        • Ruenes G.L.
        • Kajander K.J.
        • Brewer K.L.
        Excitotoxic spinal cord injury: Behavioral and morphological characteristics of a central pain model.
        Pain. 1998; 75: 141-155
        • Yu C.G.
        • Yezierski R.P.
        Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury.
        Brain Res Mol Brain Res. 2005; 138: 244-255
        • Zhang H.
        • Xie W.
        • Xie Y.
        Spinal cord injury triggers sensitization of wide dynamic range dorsal horn neurons in segments rostral to the injury.
        Brain Res. 2005; 1055: 103-110
        • Zhang Y.P.
        • Iannotti C.
        • Shields L.B.
        • Han Y.
        • Burke D.A.
        • Xu X.M.
        • Shields C.B.
        Dural closure, cord approximation, and clot removal: Enhancement of tissue sparing in a novel laceration spinal cord injury model.
        J Neurosurg. 2004; 100: 343-352
        • Zhao P.
        • Waxman S.G.
        • Hains B.C.
        Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine chemokine ligand 21.
        J Neurosci. 2007; 27: 8893-8902