Chronic Pain after Clip-Compression Injury of the Rat Spinal Cord

doi:10.1006/exnr.2002.8026

Experimental Neurology

Volume 178, Issue 1, November 2002, Pages 33-48

https://doi.org/10.1006/exnr.2002.8026 Get rights and content

Abstract

Chronic tactile allodynia and hyperalgesia are frequent complications of spinal cord injury (SCI) with poorly understood mechanisms. Possible causes are plastic changes in the central arbors of nociceptive and nonnociceptive primary sensory neurons and changes in descending modulatory serotonergic pathways. A clinically relevant clip-compression model of SCI in the rat was used to investigate putative mechanisms of chronic pain. Behavioral testing (n = 18 rats) demonstrated that moderate (35 g) or severe (50 g) SCI at the 12th thoracic spinal segment (T-12) reliably produces chronic tactile allodynia and hyperalgesia that can be evoked from the hindpaws and back. Quantitative morphometry (n = 37) revealed no changes after SCI in the density or distribution of Aβ-, Aδ-, and C-fiber central arbors of primary sensory neurons within the thoracolumbar segments T-6 to L-4. This observation rules out a mandatory relationship between pain-related behaviors and changes in the distribution or density of central afferent arbors. The area of serotonin immunoreactivity in the dorsal horn (n = 12) decreased caudal to the injury site (L1–4) and increased threefold rostral to it (T9–11). The decreased serotonin and presence of tactile allodynia and hyperalgesia caudal to the injury are consistent with disruption of descending antinociceptive serotonergic tracts that modulate pain transmission. The functional significance of the increased serotonin in rostral segments may relate to the development of tactile allodynia as serotonin also has known pronociceptive actions. Changes in the descending serotonergic pathway require further investigation, as a disruption of the balance of serotonergic input rostral and caudal to the injury site may contribute to the etiology of chronic pain after SCI.

References (70)

Z. Ali et al.
The role of 5HT3 in nociceptive processing in the rat spinal cord: Results from behavioural and electrophysiological studies
Neurosci. Lett.
(1996)
L. Bardin et al.
Effect of intrathecal administration of serotonin in chronic pain models in rats
Eur. J Pharmacol.
(2000)
B.S Bregman
Development of serotonin immunoreactivity in the rat spinal cord and its plasticity after neonatal spinal cord lesions
Dev. Brain Res.
(1987)
B.S. Bregman et al.
Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat
Exp. Neurol.
(1997)
M.D. Christensen et al.
Mechanical and thermal allodynia in chronic central pain following spinal cord injury
Pain
(1996)
M.D. Christensen et al.
Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat
Exp. Neurol.
(1997)
R. Defrin et al.
Characterization of chronic pain and somatosensory function in spinal cord injury subjects
Pain
(2001)
K.D. Dougherty et al.
Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury
Neurobiol. Dis.
(2000)
G.M. Drew et al.
Responses of spinal neurones to cutaneous and dorsal root stimuli in rats with mechanical allodynia after contusive spinal cord injury
Brain Res.
(2001)
M.J. Eaton et al.
Lumbar transplants of immortalized serotonergic neurons alleviate chronic neuropathic pain
Pain
(1997)

N. El-Yassir et al.

A 5-HT1-type receptor mediates the antinociceptive effect of nucleus raphe magnus stimulation in the rat

Brain Res.

(1990)

A.I. Faden et al.

Use of serotonin immunocytochemistry as a marker of injury severity after experimental spinal trauma in rats

Brain Res.

(1988)

M.G. Fehlings et al.

The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury

Exp. Neurol.

(1995)

H.J. Gould et al.

A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain

Brain Res.

(2000)

B.C. Hains et al.

Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: Involvement in chronic central pain after spinal hemisection in the rat

Exp. Neurol.

(2002)

B.C. Hains et al.

Subdural engraftment of serotonergic neurons following spinal hemisection restores spinal serotonin, downregulates serotonin transporter, and increases BDNF tissue content in rat

Brain Res.

(2001)

B.C. Hains et al.

Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat

Exp. Neurol.

(2001)

J.X. Hao et al.

Photochemically induced transient spinal ischemia induces behavioural hypersensitivity to mechanical and cold stimuli, but not to noxious-heat stimuli, in the rat

Exp. Neurol.

(1992)

J.C. Huang et al.

Identification of 5-hydroxytryptamine binding site subtypes in rat spinal cord

Brain Res.

(1987)

J.E. Jacob et al.

Autonomic dysreflexia in a mouse model of spinal cord injury

Neuroscience

(2001)

V.R. King et al.

TrkA, trkB, and trkC messenger RNA expression by bulbospinal cells of the rat

Neuroscience

(1999)

N.R. Krenz et al.

Sprouting of primary afferent fibers after spinal cord transection in the rat

Neuroscience

(1998)

A.M. Laporte et al.

Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HT2A and 5-HT3 receptors in the aged human spinal cord

J. Chem. Neuroanat.

(1996)

P. Li et al.

Cholinergic, noradrenergic, and serotonergic inhibition of fast synaptic transmission in spinal lumbar dorsal horn of rat

Brain Res. Bull.

(2001)

Q.P. Ma et al.

Resection of sciatic nerve re-triggers central sprouting of A-fibre primary afferents in the rat

Neurosci. Lett.

(2000)

D.L. McNeill et al.

Intraspinal sprouting of calcitonin gene-related peptide containing primary afferents after deafferentation in the rat

Exp. Neurol.

(1991)

R. Nashmi et al.

Changes in axonal physiology and morphology after chronic compressive injury of the rat thoracic spinal cord

Neuroscience

(2001)

T. Oyama et al.

Dual effect of serotonin on formalin-induced nociception in the rat spinal cord

Neurosci. Res.

(1996)

D.H. Rintala et al.

Chronic pain in a community-based sample of men with spinal cord injury: Prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being

Arch. Phys. Med. Rehabil.

(1998)

W.D. Snider et al.

Tackling pain at the source: New ideas about nociceptors

Neuron

(1998)

F. Svendsen et al.

Long term potentiation of single WDR neurons in spinalized rats

Brain Res.

(1999)

D.M White

Neurotrophin-3 antisense oligonucleotide attenuates nerve injury-induced abeta-fibre sprouting

Brain Res.

(2000)

B. Zhang et al.

Proliferation of SP- and 5HT-containing terminals in lamina II of rat spinal cord following dorsal rhizotomy: Quantitative EM-immunocytochemical studies

Exp. Neurol.

(1993)

S.K. Agrawal et al.

Mechanisms of secondary injury to spinal cord axons in vitro role Na⁺, Na⁺–K⁺-ATPase, the Na⁺–H⁺ exchanger, and the Na⁺–Ca⁺ exchanger

J. Neurosci.

(1996)

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Spinal cord injury (SCI) often results in permanent functional loss due to a series of degenerative events including cell death, axonal damage, and the upregulation of inhibitory proteins that impede regeneration. Repulsive Guidance Molecule A (RGMa) is a potent inhibitor of axonal growth that is rapidly upregulated following injury in both the rodent and human central nervous system (CNS). Previously, we showed that monoclonal antibodies that specifically block inhibitory RGMa signaling promote neuroprotective and regenerative effects when administered acutely in a clinically relevant rat model of thoracic SCI. However, it is unknown whether systemic administration of RGMa blocking antibodies are effective for SCI after delayed administration. Here, we administered elezanumab, a human monoclonal antibody targeting RGMa, intravenously either acutely or at 3 h or 24 h following thoracic clip impact-compression SCI. Rats treated with elezanumab acutely and at 3 h post-injury showed improvements in overground locomotion and fine motor function and gait. Rats treated 24 h post-SCI trended towards better recovery demonstrating significantly greater stride length and swing speed. Treated rats also showed greater tissue preservation with reduced lesion areas. As seen with acute treatment, delayed administration of elezanumab at 3 h post-SCI also increased perilesional neuronal sparing and serotonergic and corticospinal axonal plasticity. In addition, all elezanumab treated rats showed earlier spontaneous voiding ability and less post-trauma bladder wall hypertrophy. Together, our data demonstrate the therapeutic efficacy of delayed systemic administration of elezanumab in a rat model of SCI, and uncovers a new role for RGMa inhibition in bladder recovery following SCI.
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Regular ArticleChronic Pain after Clip-Compression Injury of the Rat Spinal Cord

Abstract

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Pain

Neurobiol. Dis.

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Pain

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Exp. Neurol.

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Regular Article
Chronic Pain after Clip-Compression Injury of the Rat Spinal Cord

Mechanisms of secondary injury to spinal cord axons in vitro role Na⁺, Na⁺–K⁺-ATPase, the Na⁺–H⁺ exchanger, and the Na⁺–Ca⁺ exchanger