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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: (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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