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Neuropathic pain after spinal cord injury: the impact of sensorimotor activity

Nees, Timo A.; Finnerup, Nanna B.; Blesch, Armin; Weidner, Norbert

doi: 10.1097/j.pain.0000000000000783
Topical Review
Editor's Choice

aSpinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany

bDepartment of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark

cIndiana Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery and Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN, USA

Corresponding author. Address: Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, Heidelberg 69118, Germany. Tel.: +49-6221-5626322; fax: +49-6221-5626345. E-mail address: norbert.weidner@med.uni-heidelberg.de (N. Weidner).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received July 20, 2016

Received in revised form October 07, 2016

Accepted November 03, 2016

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1. Clinical relevance of spinal cord injury pain

Spinal cord injury (SCI) results in severe sensory, motor, and autonomic dysfunction frequently followed by spasticity and neuropathic pain (NP).

Neuropathic pain can arise as a direct result of the damaged peripheral or central somatosensory nervous system. A prospective study applying the new Spinal Cord Injury Pain Classification11 reported pain in 80% of patients with traumatic SCI.38 Approximately, 40% to 60% of all SCI patients develop NP at or below the level of injury2,12,38,81,91 and half of them report pain levels as moderate to severe.38,81 Neuropathic pain that emerges within the first year after SCI2,37,38 tends to become chronic37,81 and is characterized by sensory deficits, spontaneous, or stimulus-evoked pain, including allodynia and hyperalgesia and may be associated with dysaesthesia and paresthesia.11,35 Neuropathic pain influences life beyond pain sensation impairing rehabilitation and quality of life.1,71,79,92

Current treatment approaches try to encompass most of the biopsychosocial components of NP. Antiepileptics and tricyclic antidepressants are the mainstay of NP treatment,3,68,74,80 which reduce NP by around 50% at best.79 Adverse effects limiting patient compliance are not uncommon.35,68,80

Emerging evidence supports sensorimotor activity as a beneficial approach for modulating NP in both animals and humans. Conceptually, SCI leading to reduced/absent motor output, namely impaired/absent walking/standing/sitting function, results in dramatically reduced and/or inadequate sensory stimulation of proprioceptive and cutaneous sensory afferents despite the integrity of respective pathways caudal to the spinal injury level. Sensory deprivation in turn might induce maladaptive remodeling of the spinal circuitry to result in hyperexcitability and NP (Fig. 1). Indeed, immobilization and bed rest are sufficient to induce altered sensorimotor responses in rodents84 and disturbed mechano- and thermosensitivity in human subjects,83 even without obvious damage to the nervous system.83,84 Forearm immobilization in healthy humans causes cold and mechanical hyperalgesia83 and rats with immobilized hindlimbs developed decreased paw withdrawal thresholds to mechanical stimulation.84 Interestingly, ankle joint immobilization in able-bodied humans resulted in decreased presynaptic inhibition of soleus muscle Ia afferents indicating that disuse provokes maladaptive alterations in spinal circuits controlling the sensory input to the spinal cord.62

Figure 1

Figure 1

Consequently, therapeutic sensorimotor activation paradigms, which can substitute for the missing physiological stimulation, eg, through means of walking and standing, could potentially reverse maladaptive structural changes caudal to the spinal injury level and ameliorate/prevent neuropathic pain after SCI.26,39,53,54,64,66 In principle, any kind of exercise, which provides sensory input caudal to the injury level (light touch, proprioceptive, thermal or pain stimuli) ideally associated with a defined motor output (walking, standing, swimming, cycling, functional electrical stimulation driven cycling), might be sufficient to promote respective effects.

Overall, both, complete and incomplete SCI patients suffer from neuropathic pain. Can both, patients with incomplete and complete SCI, respond to sensorimotor activation? It is known that in the majority of sensorimotor complete individuals (American Spinal Injury Association Impairment Scale A—AIS-A), numerous axons are spared (so called discomplete SCI) and therefore capable to transmit below level sensory signals to supraspinal levels.36,56 Therefore, even complete SCI patients may have the potential to respond to activation paradigms, which modulate maladaptive rearrangement caudal to the injury. However, in motor complete patients, only sensorimotor activity paradigms, which do not require voluntary motor output from the patient, are feasible, eg, passive cycling, functional electrical stimulation cycling, robot-assisted body-weight supported treadmill training, or vibration therapy. In incomplete SCI patients, active exercises such as unsupported treadmill training, overground walking or active cycling can also be considered.

This review will primarily focus on structural/functional changes at the spinal level and consequently on interventions targeting the neuronal circuitry caudal to the injury level.

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2. Mechanisms underlying neuropathic pain after spinal cord injury

Maladaptive neuroplasticity along the entire neuro-axis and associated peripheral and central sensitization leading to neuronal hyperexcitability are considered main drivers in the development of NP.35,93 Correlates of spinal hyperexcitability such as mechanical allodynia and cold-evoked dysesthesia have been identified as potential predictors of the onset of below-level NP.38,96

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2.1. Changes related to primary sensory neurons

Within the spinal circuitry, dynamic alterations in dorsal root ganglia and the dorsal horn may contribute to NP. Experimental SCI can result in peripheral sensitization indicated by increased spontaneous activity of primary nociceptors and decreased activation thresholds to mechanical and thermal stimulation.13 Long-lasting spontaneous activity of nociceptors and persistent pain seem to be maintained by upregulation of Nav1.8 channels in primary afferents,95 continuing cAMP-PKA signaling6 and increased expression of TRPV1 in dorsal root ganglia.94 Central neuroinflammatory processes after SCI might trigger nociceptors to become hyperactive.87 Vice versa the hyperactive state of primary sensory neurons promotes central sensitization and hyperexcitability of dorsal horn neurons.13

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2.2. Changes related to the dorsal horn

Electrophysiological studies in different SCI models revealed that NP is associated with hyperexcitability of dorsal horn neurons30,49 mediated by excessive release of glutamate60 and upregulation of various glutamate receptors,41,43 expression changes of voltage-gated sodium and calcium channels in dorsal horn neurons8,46,47 as well as release of inflammatory mediators and neuron-glia interactions.4,19,42,48,77,97 In particular, brain-derived neurotrophic factor (BDNF) released by activated microglia causes a downregulation of the potassium chloride cotransporter 2 (KCC2) in neurons of the superficial dorsal horn.21,22 This in turn results in disinhibition of spinal output neurons and mechanical allodynia by reducing the gamma-aminobutyric acid-ergic tone of inhibitory interneurons.61 In general, disinhibition resulting from a loss of segmental inhibitory gamma-aminobutyric acid- and glycinergic interneurons or a disruption of inhibiting descending fibers can lead to mechanical and thermal hypersensitivity after SCI.5,31,33,44,51,63 Furthermore, numerous studies provide profound evidence that structural rearrangement of both peptidergic (calcitonin gene-related peptide = CGRP) and nonpeptidergic (isolectin B4 = IB4) afferents plays a pivotal role in NP.25,26,45,57,58,66,70,89,98

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3. Sensorimotor activity in the treatment of neuropathic pain

3.1. Preclinical evidence

To date, only few rodent studies have assessed the effect of physical activity on NP-like behavior in experimental SCI (Table 1).25,26,32,54,66,88 One should keep in mind that assessment in animal models is based on behavioral correlates. Mechanical, thermal, and cold sensitivity are determined to identify altered sensation in states of neuropathic pain. However, in the context of SCI, stimulus evoked behavior might only reflect pathologically enhanced mono- or polysynaptic reflex activity indicating spasticity. The majority of studies looking at NP and sensorimotor activity used rats and various incomplete SCI models (Table 1). Rats receiving an incomplete cervical SCI26 and mice after an incomplete thoracic SCI66 developed at-26 and below-level66 mechanical and thermal hypersensitivity. Decreased paw withdrawal thresholds to mechanical stimuli were also evident three weeks after an incomplete midthoracic SCI in rats.54 Irrespective of the injury model and species, sensorimotor activity in form of moderate locomotor treadmill training significantly reduced paw withdrawal to mechanical stimuli as indicator of NP. Interestingly, all 3 studies26,54,66 shared comparable training paradigms: (1) early-onset of exercise within the first week after SCI, (2) moderate training intensity (20-30 min/d), and (3) exercise periods of at least 5 weeks. Other exercise paradigms, including swimming and stance training had only transient or no effects on SCI-induced allodynia suggesting that rhythmic stimulation of proprioceptive and mechanosensory afferents together with weight bearing might be necessary to reduce mechanical hypersensitivity.54 In conclusion, the results support moderate early-onset treadmill training as means to ameliorate behavioral correlates of NP. Recently, the effect of a 12-week locomotor treadmill training was evaluated in rats with an incomplete thoracic SCI.32 Animals developed below level heat hyperalgesia as well as mechanical and cold allodynia. To assess both prevention and reversal of NP, training was initiated 5 days or 3 weeks after SCI. In this study, sensorimotor activity did not only prevent, but also reversed established signs of NP including abnormal temperature sensations.32 The attenuation of cold hypersensitivity was preserved for at least one month after cessation of training, whereas signs of heat hyperalgesia and mechanical allodynia reappeared within 2 to 3 weeks after training conclusion.32

Table 1

Table 1

In contrast, some evidence suggests that physical activity might induce hypersensitivity after SCI.25,34 For example, in rats neither initiation of forced wheel running at the onset of tactile allodynia (14 days after cervical SCI) nor after sensory disturbances have fully developed (28 days postinjury) reduced signs of mechanical allodynia. Exercise even induced significant hypersensitivity in injured animals without NP at the time training was started.25 Hence, the time point of initiating sensorimotor activity might be crucial and may depend on the level and severity of injury.

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3.2. Clinical evidence

In an exploratory study, around 60% of wheelchair-dependent mostly sensorimotor complete paraplegic patients with NP reported pain amelioration after intensive training on a seated double-poling ergometer, which provides sensory input to the lemniscal system, however, in respect to motor output only passive leg movement. Supervised intensive interval training (1 hour, 3×/week, 10 weeks) decreased median pain intensity scores.67 Small case studies with a bionic exoskeletal walking device or a neurologic controlled hybrid assistive limb exoskeleton in chronic sensorimotor complete SCI subjects reported a significant reduction of pain severity scores (6-12 weeks, 3-5 sessions/week) in patients with NP.23,59

Taken together, respective studies suggest that well-dosed physical activity should be considered as a possible approach to treat chronic NP. At this point, preclinical evidence for the efficacy of sensorimotor activity only exists in incomplete SCI models, whereas the majority of human subjects exposed to comparable exercises suffer from complete SCI. Randomized controlled studies need to confirm the effects of sensorimotor activation paradigms to treat NP in defined—incomplete and complete—SCI populations. Animal studies should elucidate, whether complete SCI models (eg, contusion vs complete transection) equally respond to sensorimotor activity. Of course, to implement appropriate sensorimotor activation paradigms in animals with complete hindlimb paralysis is challenging. Moreover, limited compliance, adherence as well as feasibility and economic burden might be other problems to implement sensorimotor activity as a nonpharmacological therapy.27,52 Exercise paradigms suitable for home use with regular monitoring of compliance and intensity might be a step towards broader inclusion of SCI patients and maintenance of long-term effects.29,75

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4. Mechanisms of sensorimotor activity to ameliorate neuropathic pain after spinal cord injury

Sensorimotor activity has systemic effects on the cardiovascular, endocrine, immune, musculoskeletal, and nervous system. Accordingly, mechanisms mediating the specific training effect might be complex.

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4.1. Modulation of maladaptive plasticity

In SCI, locomotor training seems to reduce SCI-induced apoptosis at55 and to increase expression of neuroplasticity-associated genes below the injury site.78 Sensorimotor activity has been reported to modulate structural alterations in the spinal circuitry caudal to the level of injury. More specifically, training-induced amelioration of pain-like behavior in SCI was paralleled by reduced CGRP-labeling density in laminae III-IV of the lumbar spinal cord demonstrating that aberrant plasticity of peptidergic C-/A-δ fibers after SCI can be modulated by sensorimotor activation of the spinal circuitry below the lesion.66 Similarly, exercise-induced prevention of IB4 positive nociceptive fiber sprouting after SCI was reported to prevent the development of NP.26 Sprouting afferents gaining access to circuits that normally process nonnoxious mechanical stimuli or misconnections between incoming sensory fibers and spinal interneurons might lead to central sensitization and NP. Indeed, hyperexcitability of the below-level spinal circuitry and its modulation through sensorimotor input has been reported. Passive cycling reduced hyperexcitability of the extensor monosynaptic reflex in spinalized rats16 and restored low frequency-dependent depression of the H-reflex–an important electrophysiological sign for the integrity of the spinal circuitry.73

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4.2. Mediators modulating maladaptive plasticity

Exercise-induced pain amelioration has been related to increases of endogenous opioids in brainstem regions,82 decreased spinal microglia and astrocyte activation18 resulting in reduced release of pro-inflammatory cytokines15,28,69 and increased spinal expression of the neuroprotective heat shock protein 72.14 It is conceivable that training-induced effects on primary afferents are mediated by altered neurotrophic factor expression after injury and/or training.7,20,39,55,86 However, the role of neurotrophic factors in NP remains controversial. Neurotrophic factors are involved in neuronal survival, axon growth, synaptic plasticity, and can alter spinal circuits.9,90 Their levels are known to change after injury and/or exercise.34,72 Sensorimotor activity increases spinal BDNF mRNA and protein levels and plasticity-related effector molecules of BDNF.39 Spinal cord injury, in contrast, reduced BDNF mRNA in the spinal cord.54 Hence, restoring injury-induced decreases of spinal BDNF levels through sensorimotor activity might modulate maladaptive plasticity and ameliorate NP. Indeed, training-mediated normalization of BDNF mRNA expression in spinal cord segments corresponding to pain dermatomes has been linked to decreased mechanical allodynia.54 Similarly, restoration of spinal glial cell-line derived neurotrophic factor protein levels is associated with amelioration of mechanical hypersensitivity and reduced maladaptive sprouting of nociceptive fibers.26

Conversely, early-onset exercise has been suggested to result in BDNF-dependent C-fiber sprouting and mechanical hypersensitivity.34 Due to the conflicting results, the role of BDNF in NP and sensorimotor activity needs further investigations. For nerve growth factor, which is upregulated after SCI and perhaps the most potent neurotrophic factor influencing CGRP positive fiber sprouting, no clear regulation by training has been observed to date.10,17,55 Further studies are required to elucidate the interactions between neurotrophic factors, SCI-induced fiber changes, NP, and sensorimotor activation.

Decreased central neuroinflammation might be another effect of sensorimotor activity to modulate maladaptive plasticity and NP below the lesion. It is known that inflammatory processes after SCI, including activation of microglial and astroglial cells, increases in tumor necrosis factor α, interleukin-1β and matrix metalloproteinase-9 occur remote from the injury site and contribute to below-level NP.24,48,50 Pharmacological inhibition of microglia and astroglia activation as well as impairment of neuron-glia interactions reduce below-level NP.42,48,97 Sensorimotor activity might attenuate inflammatory responses as well.18,40,65,76,85 Thus, stimulating the below-level spinal circuitry could lead to decreased neuroinflammation which might result in reduced hyperexcitability of dorsal horn neurons and primary nociceptors.

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5. Conclusion

The majority of experimental and clinical studies support sensorimotor activity as effective means for ameliorating NP. Despite promising results in preclinical studies, studies in human SCI subjects are inconclusive at this point. In view of mostly ineffective conventional NP treatments and the tremendous impact of NP on patients' life, more comprehensive efforts are needed to evaluate the potential of different sensorimotor activity paradigms in the treatment of NP. Mouse SCI models have the potential to further strengthen emerging evidence and to unravel the mechanisms of training effects. In contrast to rats, mouse models provide the unique chance to conclusively dissect the molecular and cellular mechanisms leading to NP through the use of transgenic mouse lines and genetic manipulation. Furthermore, essential components of training paradigms need to be identified by varying timing, quantity, and quality, both in incomplete and complete SCI.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Supported by grants from the Deutsche Forschungsgemeinschaft (SFB1158), a Medical Doctor Scholarship Award from the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology to T. A. Nees and by the Indiana University Health—Indiana University School of Medicine Strategic Research Initiative to A. Blesch.

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References

[1]. Andresen SR, Biering-Sorensen F, Hagen EM, Nielsen JF, Bach FW, Finnerup NB. Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark. Spinal Cord 2016;54:973–79.
[2]. Ataoglu E, Tiftik T, Kara M, Tunc H, Ersoz M, Akkus S. Effects of chronic pain on quality of life and depression in patients with spinal cord injury. Spinal Cord 2013;51:23–6.
[3]. Baastrup C, Finnerup NB. Pharmacological management of neuropathic pain following spinal cord injury. CNS Drugs 2008;22:455–75.
[4]. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009;139:267–84.
[5]. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984;7:309–38.
[6]. Bavencoffe A, Li Y, Wu Z, Yang Q, Herrera J, Kennedy EJ, Walters ET. Persistent electrical activity in primary nociceptors after spinal cord injury is maintained by Scaffolded Adenylyl Cyclase and Protein Kinase A and is associated with altered Adenylyl Cyclase regulation. J Neurosci 2016;36:1660–8.
[7]. Beaumont E, Kaloustian S, Rousseau G, Cormery B. Training improves the electrophysiological properties of lumbar neurons and locomotion after thoracic spinal cord injury in rats. Neurosci Res 2008;62:147–54.
[8]. Boroujerdi A, Zeng J, Sharp K, Kim D, Steward O, Luo ZD. Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states. PAIN 2011;152:649–55.
[9]. Boyce VS, Mendell LM. Neurotrophins and spinal circuit function. Front Neural Circuits 2014;8:59.
[10]. Brown A, Ricci MJ, Weaver LC. NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 2004;188:115–27.
[11]. Bryce TN, Biering-Sorensen F, Finnerup NB, Cardenas DD, Defrin R, Lundeberg T, Norrbrink C, Richards JS, Siddall P, Stripling T, Treede RD, Waxman SG, Widerstrom-Noga E, Yezierski RP, Dijkers M. International spinal cord injury pain classification: part I. Background and description. March 6–7, 2009. Spinal Cord 2012;50:413–17.
[12]. Burke D, Fullen BM, Stokes D, Lennon O. Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur J Pain 2017;21:29–44.
[13]. Carlton SM, Du J, Tan HY, Nesic O, Hargett GL, Bopp AC, Yamani A, Lin Q, Willis WD, Hulsebosch CE. Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury. PAIN 2009;147:265–76.
[14]. Chen YW, Hsieh PL, Chen YC, Hung CH, Cheng JT. Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats. Anesth Analg 2013;116:482–90.
[15]. Chen YW, Lin MF, Chen YC, Hung CH, Tzeng JI, Wang JJ. Exercise training attenuates postoperative pain and expression of cytokines and N-methyl-D-aspartate receptor subunit 1 in rats. Reg Anesth Pain Med 2013;38:282–8.
[16]. Chopek JW, MacDonell CW, Gardiner K, Gardiner PF. Daily passive cycling attenuates the hyperexcitability and restores the responsiveness of the extensor monosynaptic reflex to quipazine in the chronic spinally transected rat. J Neurotrauma 2014;31:1083–7.
[17]. Cobianchi S, Casals-Diaz L, Jaramillo J, Navarro X. Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury. Exp Neurol 2013;240:157–67.
[18]. Cobianchi S, Marinelli S, Florenzano F, Pavone F, Luvisetto S. Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury. Neuroscience 2010;168:273–87.
[19]. Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 2009;29:14415–22.
[20]. Cote MP, Azzam GA, Lemay MA, Zhukareva V, Houle JD. Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury. J Neurotrauma 2011;28:299–309.
[21]. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005;438:1017–21.
[22]. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 2003;424:938–42.
[23]. Cruciger O, Schildhauer TA, Meindl RC, Tegenthoff M, Schwenkreis P, Citak M, Aach M. Impact of locomotion training with a neurologic controlled hybrid assistive limb (HAL) exoskeleton on neuropathic pain and health related quality of life (HRQoL) in chronic SCI: a case study. Disabil Rehabil Assist Technol 2014:1–6.
[24]. Detloff MR, Fisher LC, McGaughy V, Longbrake EE, Popovich PG, Basso DM. Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol 2008;212:337–47.
[25]. Detloff MR, Quiros-Molina D, Javia AS, Daggubati L, Nehlsen AD, Naqvi A, Ninan V, Vannix KN, McMullen MK, Amin S, Ganzer PD, Houle JD. Delayed exercise is ineffective at reversing aberrant nociceptive afferent plasticity or neuropathic pain after spinal cord injury in rats. Neurorehabil Neural Repair 2016;30:685–700.
[26]. Detloff MR, Smith EJ, Quiros Molina D, Ganzer PD, Houle JD. Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Exp Neurol 2014;255:38–48.
[27]. Ditor DS, Latimer AE, Ginis KA, Arbour KP, McCartney N, Hicks AL. Maintenance of exercise participation in individuals with spinal cord injury: effects on quality of life, stress and pain. Spinal Cord 2003;41:446–50.
[28]. Dobson JL, McMillan J, Li L. Benefits of exercise intervention in reducing neuropathic pain. Front Cell Neurosci 2014;8:102.
[29]. Dolbow DR, Gorgey AS, Ketchum JM, Gater DR. Home-based functional electrical stimulation cycling enhances quality of life in individuals with spinal cord injury. Top Spinal Cord Inj Rehabil 2013;19:324–9.
[30]. Drew GM, Siddall PJ, Duggan AW. Responses of spinal neurones to cutaneous and dorsal root stimuli in rats with mechanical allodynia after contusive spinal cord injury. Brain Res 2001;893:59–69.
[31]. Drew GM, Siddall PJ, Duggan AW. Mechanical allodynia following contusion injury of the rat spinal cord is associated with loss of GABAergic inhibition in the dorsal horn. PAIN 2004;109:379–88.
[32]. Dugan EA, Sagen J. An intensive locomotor training paradigm improves neuropathic pain following spinal cord compression injury in rats. J Neurotrauma 2015;32:622–32.
[33]. Eaton MJ, Wolfe SQ, Martinez M, Hernandez M, Furst C, Huang J, Frydel BR, Gomez-Marin O. Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain 2007;8:33–50.
[34]. Endo T, Ajiki T, Inoue H, Kikuchi M, Yashiro T, Nakama S, Hoshino Y, Murakami T, Kobayashi E. Early exercise in spinal cord injured rats induces allodynia through TrkB signaling. Biochem Biophys Res Commun 2009;381:339–44.
[35]. Finnerup NB. Pain in patients with spinal cord injury. PAIN 2013;154(suppl 1):S71–76.
[36]. Finnerup NB, Gyldensted C, Fuglsang-Frederiksen A, Bach FW, Jensen TS. Sensory perception in complete spinal cord injury. Acta Neurol Scand 2004;109:194–9.
[37]. Finnerup NB, Jensen MP, Norrbrink C, Trok K, Johannesen IL, Jensen TS, Werhagen L. A prospective study of pain and psychological functioning following traumatic spinal cord injury. Spinal Cord 2016;54:816–21.
[38]. Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC, Jensen TS, Werhagen L. Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain 2014;15:40–8.
[39]. Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002;88:2187–95.
[40]. Griffin L, Decker MJ, Hwang JY, Wang B, Kitchen K, Ding Z, Ivy JL. Functional electrical stimulation cycling improves body composition, metabolic and neural factors in persons with spinal cord injury. J Electromyogr Kinesiol 2009;19:614–22.
[41]. Gwak YS, Hulsebosch CE. Upregulation of Group I metabotropic glutamate receptors in neurons and astrocytes in the dorsal horn following spinal cord injury. Exp Neurol 2005;195:236–43.
[42]. Gwak YS, Hulsebosch CE. Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience 2009;161:895–903.
[43]. Gwak YS, Kang J, Leem JW, Hulsebosch CE. Spinal AMPA receptor inhibition attenuates mechanical allodynia and neuronal hyperexcitability following spinal cord injury in rats. J Neurosci Res 2007;85:2352–9.
[44]. Gwak YS, Tan HY, Nam TS, Paik KS, Hulsebosch CE, Leem JW. Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma 2006;23:1111–24.
[45]. Hagg T. Collateral sprouting as a target for improved function after spinal cord injury. J Neurotrauma 2006;23:281–94.
[46]. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 2003;23:8881–92.
[47]. Hains BC, Saab CY, Waxman SG. Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. Brain 2005;128(Pt 10):2359–71.
[48]. Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 2006;26:4308–17.
[49]. Hains BC, Willis WD, Hulsebosch CE. Serotonin receptors 5-HT1A and 5-HT3 reduce hyperexcitability of dorsal horn neurons after chronic spinal cord hemisection injury in rat. Exp Brain Res 2003;149:174–86.
[50]. Hansen CN, Fisher LC, Deibert RJ, Jakeman LB, Zhang H, Noble-Haeusslein L, White S, Basso DM. Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. J Neurosci 2013;33:13101–11.
[51]. Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev 2009;60:214–25.
[52]. Hicks AL, Martin KA, Ditor DS, Latimer AE, Craven C, Bugaresti J, McCartney N. Long-term exercise training in persons with spinal cord injury: effects on strength, arm ergometry performance and psychological well-being. Spinal Cord 2003;41:34–43.
[53]. Houle JD, Cote MP. Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 2013;1279:154–63.
[54]. Hutchinson KJ, Gomez-Pinilla F, Crowe MJ, Ying Z, Basso DM. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain 2004;127(Pt 6):1403–14.
[55]. Jung SY, Kim DY, Yune TY, Shin DH, Baek SB, Kim CJ. Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med 2014;7:587–93.
[56]. Kakulas BA. A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 1999;22:119–24.
[57]. Kerr BJ, David S. Pain behaviors after spinal cord contusion injury in two commonly used mouse strains. Exp Neurol 2007;206:240–7.
[58]. Krenz NR, Weaver LC. Sprouting of primary afferent fibers after spinal cord transection in the rat. Neuroscience 1998;85:443–58.
[59]. Kressler J, Thomas CK, Field-Fote EC, Sanchez J, Widerstrom-Noga E, Cilien DC, Gant K, Ginnety K, Gonzalez H, Martinez A, Anderson KD, Nash MS. Understanding therapeutic benefits of overground bionic ambulation: exploratory case series in persons with chronic, complete spinal cord injury. Arch Phys Med Rehabil 2014;95:1878–87.e1874.
[60]. Liu D, Thangnipon W, McAdoo DJ. Excitatory amino acids rise to toxic levels upon impact injury to the rat spinal cord. Brain Res 1991;547:344–8.
[61]. Lu Y, Zheng J, Xiong L, Zimmermann M, Yang J. Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat. J Physiol 2008;586(Pt 23):5701–15.
[62]. Lundbye-Jensen J, Nielsen JB. Immobilization induces changes in presynaptic control of group Ia afferents in healthy humans. J Physiol 2008;586(Pt 17):4121–35.
[63]. Meisner JG, Marsh AD, Marsh DR. Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury. J Neurotrauma 2010;27:729–37.
[64]. Molteni R, Zheng JQ, Ying Z, Gomez-Pinilla F, Twiss JL. Voluntary exercise increases axonal regeneration from sensory neurons. Proc Natl Acad Sci U S A 2004;101:8473–8.
[65]. Neefkes-Zonneveld CR, Bakkum AJ, Bishop NC, van Tulder MW, Janssen TW. Effect of long-term physical activity and acute exercise on markers of systemic inflammation in persons with chronic spinal cord injury: a systematic review. Arch Phys Med Rehabil 2015;96:30–42.
[66]. Nees TA, Tappe-Theodor A, Sliwinski C, Motsch M, Rupp R, Kuner R, Weidner N, Blesch A. Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury. PAIN 2016;157:687–97.
[67]. Norrbrink C, Lindberg T, Wahman K, Bjerkefors A. Effects of an exercise programme on musculoskeletal and neuropathic pain after spinal cord injury–results from a seated double-poling ergometer study. Spinal Cord 2012;50:457–61.
[68]. Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury: a randomized, double-blind, placebo-controlled trial. Clin J Pain 2009;25:177–84.
[69]. O'Donnell J, Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem Res 2012;37:2496–512.
[70]. Ondarza AB, Ye Z, Hulsebosch CE. Direct evidence of primary afferent sprouting in distant segments following spinal cord injury in the rat: colocalization of GAP-43 and CGRP. Exp Neurol 2003;184:373–80.
[71]. Putzke JD, Richards JS, Hicken BL, DeVivo MJ. Interference due to pain following spinal cord injury: important predictors and impact on quality of life. PAIN 2002;100:231–42.
[72]. Ramer MS, Priestley JV, McMahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature 2000;403:312–16.
[73]. Reese NB, Skinner RD, Mitchell D, Yates C, Barnes CN, Kiser TS, Garcia-Rill E. Restoration of frequency-dependent depression of the H-reflex by passive exercise in spinal rats. Spinal Cord 2006;44:28–34.
[74]. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil 2007;88:1547–60.
[75]. Rupp R, Schließmann D, Plewa H, Schuld C, Gerner HJ, Weidner N, Hofer EP, Knestel M. Safety and efficacy of at-home robotic locomotion therapy in individuals with chronic incomplete spinal cord injury: a prospective, pre-post intervention study. PLoS One 2015;10:e0119167.
[76]. Sandrow-Feinberg HR, Izzi J, Shumsky JS, Zhukareva V, Houle JD. Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury. J Neurotrauma 2009;26:721–31.
[77]. Schmitt AB, Buss A, Breuer S, Brook GA, Pech K, Martin D, Schoenen J, Noth J, Love S, Schroder JM, Kreutzberg GW, Nacimiento W. Major histocompatibility complex class II expression by activated microglia caudal to lesions of descending tracts in the human spinal cord is not associated with a T cell response. Acta Neuropathol 2000;100:528–36.
[78]. Shin HY, Kim H, Kwon MJ, Hwang DH, Lee K, Kim BG. Molecular and cellular changes in the lumbar spinal cord following thoracic injury: regulation by treadmill locomotor training. PLoS One 2014;9:e88215.
[79]. Siddall PJ. Management of neuropathic pain following spinal cord injury: now and in the future. Spinal Cord 2009;47:352–9.
[80]. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 2006;67:1792–800.
[81]. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. PAIN 2003;103:249–57.
[82]. Stagg NJ, Mata HP, Ibrahim MM, Henriksen EJ, Porreca F, Vanderah TW, Philip Malan T Jr. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiology 2011;114:940–8.
[83]. Terkelsen AJ, Bach FW, Jensen TS. Experimental forearm immobilization in humans induces cold and mechanical hyperalgesia. Anesthesiology 2008;109:297–307.
[84]. Trierweiler J, Gottert DN, Gehlen G. Evaluation of mechanical allodynia in an animal immobilization model using the von frey method. J Manipulative Physiol Ther 2012;35:18–25.
[85]. Turiel M, Sitia S, Cicala S, Magagnin V, Bo I, Porta A, Caiani E, Ricci C, Licari V, De Gennaro Colonna V, Tomasoni L. Robotic treadmill training improves cardiovascular function in spinal cord injury patients. Int J Cardiol 2011;149:323–9.
[86]. Vaynman S, Gomez-Pinilla F. License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins. Neurorehabil Neural Repair 2005;19:283–95.
[87]. Walters ET. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Exp Neurol 2014;258:48–61.
[88]. Ward PJ, Herrity AN, Smith RR, Willhite A, Harrison BJ, Petruska JC, Harkema SJ, Hubscher CH. Novel multi-system functional gains via task specific training in spinal cord injured male rats. J Neurotrauma 2014;31:819–33.
[89]. Weaver LC, Verghese P, Bruce JC, Fehlings MG, Krenz NR, Marsh DR. Autonomic dysreflexia and primary afferent sprouting after clip-compression injury of the rat spinal cord. J Neurotrauma 2001;18:1107–19.
[90]. Weishaupt N, Blesch A, Fouad K. BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol 2012;238:254–64.
[91]. Werhagen L, Budh CN, Hultling C, Molander C. Neuropathic pain after traumatic spinal cord injury–relations to gender, spinal level, completeness, and age at the time of injury. Spinal Cord 2004;42:665–73.
[92]. Widerstrom-Noga EG, Felipe-Cuervo E, Yezierski RP. Chronic pain after spinal injury: interference with sleep and daily activities. Arch Phys Med Rehabil 2001;82:1571–7.
[93]. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN 2011;152(suppl 3):S2–15.
[94]. Wu Z, Yang Q, Crook RJ, O'Neil RG, Walters ET. TRPV1 channels make major contributions to behavioral hypersensitivity and spontaneous activity in nociceptors after spinal cord injury. PAIN 2013;154:2130–41.
[95]. Yang Q, Wu Z, Hadden JK, Odem MA, Zuo Y, Crook RJ, Frost JA, Walters ET. Persistent pain after spinal cord injury is maintained by primary afferent activity. J Neurosci 2014;34:10765–9.
[96]. Zeilig G, Enosh S, Rubin-Asher D, Lehr B, Defrin R. The nature and course of sensory changes following spinal cord injury: predictive properties and implications on the mechanism of central pain. Brain 2012;135(Pt 2):418–30.
[97]. Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci 2007;27:2357–68.
[98]. Zinck ND, Rafuse VF, Downie JW. Sprouting of CGRP primary afferents in lumbosacral spinal cord precedes emergence of bladder activity after spinal injury. Exp Neurol 2007;204:777–90.
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